The MYH7 NM_000257.4:c.1208G>A (NP_000248.2:p.(Arg403Gln)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be Likely Pathogenic. This variant is considered to be Pathogenic by the VCEP (ClinGen Cardiomyopathy Variant Curation Expert Panel; ClinVar ID 14087).
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MYH7 encodes the beta, or slow, heavy chain of cardiac myosin, a motor protein that helps heart muscle contract, and is also found in slow-twitch skeletal muscle fibers. Changes in MYH7 are associated with familial hypertrophic cardiomyopathy, dilated cardiomyopathy, myosin storage myopathy, and Laing distal myopathy. MYH7 is not established as a cancer-associated gene.
The recorded framework is ClinGen MYH7 VCEP v2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at Moderate: missense p.Arg403Gln is at codon 403, within the MYH7 VCEP PM1 interval of codons 167-931, with HCM clinical reports.
Met at Supporting: European (non-Finnish) gnomAD v4.1 has AC=1 in AN=1,180,040, satisfying the VCEP PM2 equivalent AC≤1 in AN≥120,000 condition.
Met at strong: 20 affected Arg403Gln family members were reported across two families, exceeding the VCEP threshold of at least 7 segregations.
Met: REVEL 0.886 meets the VCEP PP3 threshold of >=0.70 for this missense variant.
Not applicable: the MYH7 VCEP prohibits PP5 under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PP1 (strong) plus PM1 (moderate) satisfy Rule11 of the MYH7 Cardiomyopathy Expert Panel framework.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1 / 1,614,220 alleles. Recorded AF 6.19494e-07. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.886. Refer to the recorded PP3/BP4 rationale for interpretation.
21 Pathogenic. ClinVar API review status: reviewed by expert panel.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen MYH7 VCEP v2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 4 not met · 8 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS4 was not assessed because the available variant-specific reports do not provide a valid paired case-control dataset for the VCEP-required OR and 95% CI evaluation; PP4, PP5, BP5, and BP6 are not applicable under the MYH7 VCEP rules.
No criteria match.
The MYH7 VCEP PM1 rule applies to missense variants in transcripts ENST00000355349 or NM_000257.4 at codons 167-931, and says not to apply the rule when additional evidence supports a phenotype other than HCM. This variant is a missense NM_000257.4:c.1208G>A (p.Arg403Gln) at codon 403, within the specified interval. The extracted clinical reports concern hypertrophic cardiomyopathy, with no evidence in the reviewed material that this variant causes another phenotype. PM1 is therefore met at Moderate.
Applicable to missense variants in _MYH7_ in the specific regions listed below (Walsh _et al._ 2019[<sup>10</sup>](#pmid_30696458)). ... 1. Transcripts ENST00000355349 & NM\_000257.4 ... 2. Codons 167-931\*. ... Data from HCM case cohorts was used to derive these cluster regions. Therefore, this rule should NOT be applied when additional evidence for the variant supports that the variant causes a phenotype other than HCM (e.g., variant seen in multiple DCM cases).
The MYH7 VCEP v2.0 PM2 rule is applicable at Supporting strength when the highest-frequency subpopulation has upper-bound 95% CI AF ≤0.00004, with the specified equivalent AC/AN conditions including AC≤1 in AN≥120,000. In gnomAD v4.1, the highest observed subpopulation is European (non-Finnish) with AC=1 and AN=1,180,040, satisfying the stated equivalent condition; the variant is also absent from gnomAD v2.1 non-cancer. The disease-context prerequisites in the VCEP rule are compatible with this MYH7 cardiomyopathy interpretation: prevalence no greater than 1/500, most frequent pathogenic variant no more than 2% of cases, and expected penetrance at least 50%.
The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly _et al._ 2018[<sup>11</sup>](#pmid_29300372)). ... A threshold of **≤0.00004** in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule. ... Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following: * **Allele Count (AC) in Allele Number (AN)** * **≤1 in ≥120,000** * **≤2 in ≥160,000** * **≤3 in ≥195,000** * **≤4 in ≥230,000**
Variant-specific family studies report genotype-positive individuals with clinically affected HCM in multiple families. PMID:12975413 reports 14 affected members with the Arg403Gln defect in one family and six affected members with the defect in a second family, for 20 reported affected genotype-positive individuals; PMID:1638703 reports affected carriers in kindred 2002 with ECG and echocardiographic evaluation; and PMID:1975517 reports perfect cosegregation in a French Canadian familial HCM family. The VCEP strong threshold is at least 7 segregations, and only genotype-positive/phenotype-positive individuals are counted. The reported 20 affected Arg403Gln family members exceed that threshold, although the papers do not provide a formal LOD calculation.
Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥7 segregations** (LOD score of 2.1) for **STRONG**. ... Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance. ... Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.
VCEP scope: computational evidence for this missense variant may use REVEL for predicted protein impact and SpliceAI for predicted splice impact; the rule does not require both predictions to be positive, and predictions must not be double-counted as independent criteria. The VCEP recommends REVEL >=0.70 for PP3. REVEL is 0.886, which meets the VCEP PP3 threshold. SpliceAI is available and reports a maximum delta score of 0.018, but this separate splice prediction is not counted as an additional PP3 criterion.
As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors. ... Use of REVEL (Ioannidis _et al._ 2016[<sup>14</sup>](#pmid_27666373)) is recommended at thresholds of **≥0.70 for PP3**. ... Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data. ... Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions. ... [SpliceAI](https://spliceailookup.broadinstitute.org)[<sup>13</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
Expert panel ClinGen Cardiomyopathy Variant Curation Expert Panel classified as Pathogenic.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The MYH7 VCEP marks PS1 applicable at Strong and defers to ACMG/AMP 2015. The target is NM_000257.4:c.1208G>A (p.Arg403Gln). The variant-specific extracted reports reviewed here describe this same nucleotide change, and none documents a distinct nucleotide change producing p.Arg403Gln. Therefore, the required previously established pathogenic same-amino-acid change caused by a different nucleotide change is not met.
No cardiomyopathy specifications. Apply as outlined by Richards _et al_. 2015[<sup>1</sup>](#pmid_25741868). ... Example of when rule should NOT be applied. NM\_000256.3(_MYBPC3_): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.
The MYH7 VCEP permits PM5 at Moderate only for a different missense variant at the same codon classified as pathogenic without PM5, or at Supporting for a different missense variant classified as likely pathogenic without PM5, with comparable or greater impact. The PM5 comparator collection contains five candidates but zero same-residue candidates, and the extracted reports reviewed here describe the target p.Arg403Gln rather than a different missense substitution at codon 403. PM5 is not met.
This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as _pathogenic_ using these modified guidelines without application of PM5. ... The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). ... PM5 should not be combined with PM1. If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.
The available family studies do not report multiple affected non-carriers. One 9-month-old genotype-positive individual in kindred 2002 had a normal ECG and echocardiogram, but this is a genotype-positive/phenotype-negative observation in an infant and is not a non-segregation among affected family members. The VCEP requires at least two non-segregations highly unlikely to represent phenocopies or alternate disease-causing variants before applying BS4 strong. That requirement is not met.
Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. ... Because of these possibilities, **multiple (≥2) non-segregations** that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) **are required to apply this rule**. A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).
VCEP scope: computational evidence for this missense variant may use REVEL for predicted protein impact and SpliceAI for predicted splice impact; the rule does not require both predictions to be negative, and predictions must not be double-counted as independent criteria. The VCEP recommends REVEL <=0.40 for BP4. REVEL is 0.886, so the named protein-impact predictor does not meet BP4. SpliceAI predicts no significant splice impact with a maximum delta score of 0.018, but that result cannot override the VCEP REVEL requirement or independently establish BP4.
As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors. ... Use of REVEL (Ioannidis et al. 2016[<sup>14</sup>](#pmid_27666373)) is recommended at thresholds of **≤0.40 for BP4**. ... Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data. ... Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions. ... [SpliceAI](https://spliceailookup.broadinstitute.org)[<sup>13</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
The available record contains one ClinVar submission reporting germline origin as de novo, but it does not document confirmed maternity and paternity, the proband's phenotype, a clinically evaluated unaffected family history, or exclusion of other possible disease-causing variants. The VCEP requires the phenotype to be consistent with the gene, ideally clinically evaluated parents without cardiomyopathy for strong use, and applicability generally in the absence of other possible disease-causing variants. Therefore PS2 cannot be evaluated from the available evidence.
Refer to SVI guidance on number/combination of cases required based on phenotype specificity[<sup>2</sup>](#url_c73e109e-b916-5a72-b7b1-1762446f3c11)). ... For most cardiomyopathies, it is recommended to default to **Phenotype consistency: “Phenotype consistent with gene but not highly specific”**. Clinical judgment is required for shifting to a higher or lower category. ... For use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity). ... Generally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants. If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.
The VCEP requires evaluation of studies and assays before applying functional evidence at any strength. The available case materials contain classifier-generated leads describing a transgenic rabbit model, patient metabolic measurements, and an in vitro cardiac myosin motility assay for p.Arg403Gln, but they do not provide auditable primary-source findings with the assay design, appropriate controls, reproducibility, or quantitative results needed to evaluate those studies. The VCEP specifically states that individual in vitro assays such as biochemical, myofilament, motility, or human iPSC-CM assays are unlikely to support more than Supporting evidence because no validated gold-standard assay reliably predicts the clinical phenotype. Therefore PS3 cannot be assigned from the available verified evidence; the leads require primary-source review before any strength is selected.
Evaluation of studies/assays is required prior to application of functional evidence at any strength. ... While some _in vitro_ assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype. ... As such, in the cardiomyopathy genes listed in these guidelines, data from individual _in vitro_ studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.
The governing PS4 rule requires comparative case and population-control analyses with available denominators and specifies that Supporting, Moderate, and Strong evidence require the lower 95% CI of the OR to be >=5, >=10, and >=20, respectively. The VCEP PS4 example file was searched for c.1208G>A, p.Arg403Gln, and p.R403Q and contained no entry for this variant. Literature review identified variant-specific HCM observations: 9 patients in PMID:10725281, a kindred report involving 15 relatives/carriers with a survey of 100 chromosomes in PMID:1638703, and a family report with 104 unrelated individuals screened in PMID:1975517. These reports do not provide a valid non-overlapping case denominator paired with a suitable control denominator and therefore do not permit a defensible OR and 95% CI calculation under the VCEP rule. The criterion is not assessed rather than inferred from affected-case observations alone.
Currently few well-designed case-control studies have been performed for inherited cardiomyopathies. Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). ... The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls). ... To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended: ... SUPPORTING evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be ≥5
The available record contains one ClinVar submission reporting the variant as de novo without documented maternity or paternity confirmation, which is compatible with the original PM6 concept. However, the VCEP PM6 rule requires assessment using phenotype consistency and the number/combination of cases under the cited SVI guidance, and the available record does not document the affected individual's phenotype, parental testing, or a qualifying set of cases. PM6 therefore cannot be evaluated.
Refer to SVI guidance on number/combination of cases required based on phenotype specificity[<sup>2</sup>](#url_c73e109e-b916-5a72-b7b1-1762446f3c11). ... For most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. ... See PS2 for additional considerations.
The MYH7 VCEP v2.0 BA1 rule requires a filtering allele frequency (FAF) of at least 0.001 in the gnomAD popmax subpopulation. The available gnomAD v4.1 record reports observed allele frequency 8.47429e-07 in European (non-Finnish) individuals (1/1,180,040 alleles), but grpmax FAF is not available; the observed AF cannot be substituted for the required FAF.
Allele frequency is **≥0.001** based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).
The MYH7 VCEP v2.0 BS1 rule requires a filtering allele frequency (FAF) of at least 0.0001 in the gnomAD popmax subpopulation. The available gnomAD v4.1 record reports observed allele frequency 8.47429e-07 in European (non-Finnish) individuals (1/1,180,040 alleles), but grpmax FAF is not available; the observed AF cannot be substituted for the required FAF.
Allele frequency is **≥0.0001 for** _**MYH7**_ based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).
The VCEP makes BS3 strength dependent on the PS3 specifications. The available evidence does not contain a verified functional assay demonstrating that p.Arg403Gln has no damaging effect on MYH7 protein function or splicing; the available functional-study leads instead describe potentially damaging findings and lack auditable primary-source assay details. No benign functional result with suitable controls, validation, and reproducibility is documented. BS3 therefore cannot be assigned at any strength.
See PS3 specifications.
BP2 is applicable in principle at Supporting strength, but it cannot be assessed from the available evidence. The VCEP requires another variant to be pathogenic under these specifications, phase established as trans or double heterozygosity, and at least two cases in which the phenotype is no more severe than with either variant alone. No case evidence documents a pathogenic second variant, cis/trans phase, double heterozygosity, or the required two qualifying cases for NM_000257.4:c.1208G>A (p.Arg403Gln).
Other variants must be pathogenic as defined by these specifications. Testing of parents or other informative relatives is often required to determine _cis_/_trans_ status. If a variant is seen in _trans_ (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease). * <1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares _et al._ 2015[<sup>17</sup>](#pmid_25611685)). This rule cannot be applied when the variant has only been observed in _cis_ with a pathogenic variant as its significance in isolation is unknown in this scenario. Caution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).
The MYH7 VCEP v2.0 CSPEC entry explicitly marks PVS1 as Not Applicable. The variant is NM_000257.4:c.1208G>A (NP_000248.2:p.(Arg403Gln)), a missense variant in exon 13, not a loss-of-function variant to which a PVS1 assessment could be applied under this VCEP entry.
Not Applicable
PM3 is not applicable under the MYH7 VCEP specification. The VCEP identifies MYH7-associated cardiomyopathies in this framework as autosomal dominant and explicitly excludes the recessive-disease PM3 edge cases from the current guideline.
It is acknowledged that there is increasing evidence supporting that some of these genes/variants may also be recessive (e.g., MYL2, MYL3), but addressing those edge cases was outside the scope of this current guideline.
The MYH7 VCEP v2.0 PM4 rule addresses predicted-impact downgrading for deletions/insertions and, specifically when PVS1 is not applicable, truncating variants that do not undergo NMD. This variant is a missense substitution, NM_000257.4:c.1208G>A (p.Arg403Gln), so it is outside the variant type named by the governing rule.
Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. ... For genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).
The MYH7 VCEP v2.0 explicitly marks PP2 Not applicable. Its instructions describe regional rare-missense enrichment for MYH7 as addressed by the PM1 specification rather than by independent PP2 application.
Application of this rule takes into consideration empirical data quantifying levels of rare missense variant enrichment in HCM referral cohorts compared to population-based cohorts (Walsh et al. 2019 PMID:30696458) rather than the missense constraint score in gnomAD. For MYH7, there is evidence for regional enrichment of rare missense variants (see PM1 specifications).
The MYH7 VCEP marks PP4 not applicable because inherited cardiomyopathies have high locus heterogeneity and non-genetic etiologies.
Inherited cardiomyopathies have high locus heterogeneity as well as non-genetic etiologies.
The MYH7 VCEP v2.0 CSPEC entry marks BS2 as Not applicable. Its instructions explain that inherited cardiomyopathies generally have reduced penetrance, variable expressivity, and adult onset, so the healthy-adult observation criterion is not used under this specification.
Inherited cardiomyopathies generally display reduced penetrance, variable expressivity, and adult-onset.
The MYH7 VCEP v2.0 explicitly marks BP1 Not applicable. The VCEP instruction states that, for the current genes where null variants are a known mechanism, pathogenic missense variants have also been reported; BP1 is therefore excluded for MYH7.
For the current genes where null variants are a known mechanism, pathogenic missense variants have also been reported.
The MYH7 VCEP v2.0 CSPEC entry explicitly marks BP3 as Not Applicable. The variant is a missense substitution, NM_000257.4:c.1208G>A (NP_000248.2:p.(Arg403Gln)), rather than a variant in a repeat region for which BP3 could be considered under this VCEP specification.
Not Applicable
The MYH7 VCEP marks BP5 not applicable because co-occurrence with an established pathogenic or likely pathogenic variant for a non-cardiomyopathy-related disease does not reduce the likelihood that a variant is independently disease-causing for cardiomyopathy.
Co-occurrence with an established pathogenic or likely pathogenic variant for a non-cardiomyopathy related disease does not reduce the likelihood that a variant is independently disease-causing for cardiomyopathy.
The MYH7 VCEP marks BP6 not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The VCEP limits BP7 to intronic variants outside the splice consensus sequence (-4 and +7 outward). NM_000257.4:c.1208G>A is a missense variant in exon 13, so BP7 is outside its governing scope and is not applicable; predictor results are not needed for this determination.
Also applicable to **intronic variants outside the splice consensus sequence (-4 and +7 outward)** for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved. ... Rule can be combined with BP4 to make a variant likely benign per Richards _et al._ 2015[<sup>1</sup>](#pmid_25741868).
Every interpreted variant in MYH7, mapped onto the exon structure of NM_000257.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)1 / 1,180,040 | 8.5e-07 |
This variant is present in gnomAD v4.1 (AF= 6.19494e-07; MAF= 0.00006%, 1/1614220 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47429e-07; MAF= 0.00008%, 1/1180040 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
VCEP scope: computational evidence for this missense variant may use REVEL for predicted protein impact and SpliceAI for predicted splice impact; the rule does not require both predictions to be positive, and predictions must not be double-counted as independent criteria. The VCEP recommends REVEL >=0.70 for PP3. REVEL is 0.886, which meets the VCEP PP3 threshold. SpliceAI is available and reports a maximum delta score of 0.018, but this separate splice prediction is not counted as an additional PP3 criterion.
As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors. ... Use of REVEL (Ioannidis _et al._ 2016[<sup>14</sup>](#pmid_27666373)) is recommended at thresholds of **≥0.70 for PP3**. ... Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data. ... Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions. ... [SpliceAI](https://spliceailookup.broadinstitute.org)[<sup>13</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
VCEP scope: computational evidence for this missense variant may use REVEL for predicted protein impact and SpliceAI for predicted splice impact; the rule does not require both predictions to be negative, and predictions must not be double-counted as independent criteria. The VCEP recommends REVEL <=0.40 for BP4. REVEL is 0.886, so the named protein-impact predictor does not meet BP4. SpliceAI predicts no significant splice impact with a maximum delta score of 0.018, but that result cannot override the VCEP REVEL requirement or independently establish BP4.
As many _in silico_ algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors. ... Use of REVEL (Ioannidis et al. 2016[<sup>14</sup>](#pmid_27666373)) is recommended at thresholds of **≤0.40 for BP4**. ... Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data. ... Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions. ... [SpliceAI](https://spliceailookup.broadinstitute.org)[<sup>13</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
The VCEP limits BP7 to intronic variants outside the splice consensus sequence (-4 and +7 outward). NM_000257.4:c.1208G>A is a missense variant in exon 13, so BP7 is outside its governing scope and is not applicable; predictor results are not needed for this determination.
Also applicable to **intronic variants outside the splice consensus sequence (-4 and +7 outward)** for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved. ... Rule can be combined with BP4 to make a variant likely benign per Richards _et al._ 2015[<sup>1</sup>](#pmid_25741868).
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.886. BayesDel score = 0.342791.
8 paper records listed. 3 cited in the classification.
In one family of 14 affected members with the Arg403Gln defect involving the actin binding site, there was a history of aborted sudden death in a 19 year old man, a cardiac transplant because of end stage HCM at age 30 in his father, surgical myectomy required in three family members, and sudden death before the age of 60 in three additional relatives (fig 2A).
Location Results, Predictors of survival; Table 1; Table 2; Figure 2A
Context Cohort study of 70 HCM probands with 148 family members assessed; beta-MHC exons 3-23 were screened by PCR amplification and direct DNA sequencing, followed by genotype-specific family testing and clinical, ECG, echocardiographic, pedigree, and survival analyses.
Direct sequencing in both directions of the exon 13 fragment detected a G->A transition that resulted in the replacement of an arginine by a glutamine at amino acid residue 403.
Location Table 1; Results, Identification of the Arg->Gln Mutation in Kindred 2002; Results, Disease Penetrance and Clinical Characteristics of the 403 Mutation
Context PCR amplification and SSCP analysis of MYH7 exons, bidirectional exon 13 sequencing, DdeI restriction-fragment analysis, and clinical, ECG, and echocardiographic evaluation of kindred 2002.
This missense mutation converts a highly conserved arginine residue (Arg-403) to a glutamine.
Location Abstract; Results, pp. 1002-1003, exon 13 sequencing and family segregation; Discussion, pp. 1003-1004
Context Genomic DNA and cloned beta-cardiac MHC alleles from affected and unaffected family members were analyzed by Southern blotting, DdeI restriction-fragment analysis, cloning, and exon 13 Sanger sequencing; segregation was assessed in family A.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 6.19494e-07; MAF= 0.00006%, 1/1614220 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47429e-07; MAF= 0.00008%, 1/1180040 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (21 clinical laboratories) and as Pathogenic by ClinGen Cardiomyopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 14087)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.886. BayesDel score = 0.342791.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.