The MYBPC3 NM_000256.3:c.1504C>T (NP_000247.2:p.(Arg502Trp)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Human myectomy tissue showed approximately 24% lower MyBP-C content in MYBPC3-mutant samples, including Arg502Trp, versus donor tissue. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MYBPC3 encodes a heart-specific protein that helps regulate the contraction of cardiac muscle. Changes in this gene are a common cause of familial hypertrophic cardiomyopathy, an inherited condition in which the heart muscle becomes abnormally thickened. MYBPC3 has no recognized role in cancer.
The recorded framework is ClinGen MYBPC3 VCEP v1.0. 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 Supporting: human myectomy tissue showed approximately 24% lower MyBP-C content in MYBPC3-mutant samples, including Arg502Trp, versus donor tissue.
Met at moderate: p.Arg502Trp is a missense variant at codon 502, within the VCEP-approved MYBPC3 region 485-502.
Met at supporting: gnomAD v2.1 non-cancer exomes show one Other allele (1/6,626) and zero Ashkenazi Jewish alleles, satisfying the VCEP ≤1-allele alternative.
Met at supporting: familial cosegregation produced a combined LOD score of 4.04, exceeding the VCEP supporting threshold of LOD 0.9.
No benign criterion marked as applied in the recorded assessment.
VUS: PS3 supporting, PM1 moderate, PM2 supporting, and PP1 supporting do not satisfy a MYBPC3 VCEP pathogenic or benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 233 / 1,613,896 alleles. Recorded AF 0.000144371. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 4.6324e-05; MAF= 0.00463%, 13/280632 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000140056; MAF= 0.01401%, 1/7140 alleles, homozygotes = 0); grpmax FAF= 5.237e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 5.42947116950809e-05, 1/18418 alleles, homozygotes = 0).
Recorded REVEL score: 0.640. Refer to the recorded PP3/BP4 rationale for interpretation.
32 Pathogenic · 3 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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 MYBPC3 VCEP v1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 5 not met · 7 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Only PVS1, PM4, and BP3 were adjudicated. All three are not applicable under the MYBPC3 VCEP rules: the variant is missense rather than a specified loss-of-function or protein-length-changing allele, and BP3 is explicitly excluded for the current genes.
Within this requested group, PM1 is met at moderate strength because the missense variant affects codon 502, included in the MYBPC3 VCEP's specified 485-502 cluster region.
PS1 and PM5 are not assessed because the available evidence does not establish the required distinct same-amino-acid or same-codon comparator, while PP2 and BP1 are explicitly not applicable under the VCEP.
PS4 is not met because the qualifying variant-specific case-control comparison has a 95% CI lower OR bound of 1.67, below the VCEP Supporting threshold of >=5; PP4, PP5, BP5, and BP6 are VCEP-not-applicable criteria.
BA1 and BS1 are not met because the highest available gnomAD popmax FAF, 0.000166, is below both VCEP thresholds.
BS2 is not applicable under the MYBPC3 VCEP.
PM2 is met at Supporting strength under the VCEP's ≤1-allele non-founder-population alternative.
No criteria match.
PS3 is met at Supporting strength. The VCEP states that individual in vitro studies assessing protein and/or myofilament function are unlikely to support more than Supporting evidence because no validated gold-standard assays reliably predict the clinical phenotype. PMID:19574547 directly identified Arg502Trp in a human HCM myectomy sample and measured MyBP-C protein abundance relative to actin; the MYBPC3-mutant samples, including the two missense samples, showed significantly reduced MyBP-C-to-actin ratios versus donor tissue, with approximately 24% lower MyBP-C content across MYBPC3-mutant samples. This is variant-specific human tissue functional evidence with comparator tissue, but it is not the VCEP's specified Strong splicing-assay pathway and does not justify greater than Supporting strength.
_**In vitro**_ **assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)** 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 variant is a missense change on NM_000256.3 at codon 502. The MYBPC3 VCEP limits PM1 to missense variants on ENST00000545968 or NM_000256.3 at codons 485-502 and 1248-1266; codon 502 is included in the first region. The available variant-specific literature concerns HCM and provides no evidence that this variant causes a phenotype other than HCM, so the VCEP exclusion is not triggered. The VCEP domain_tables entry for MYBPC3 is empty, so there is no additional authoritative domain-table entry to check.
Applicable to missense variants in _MYBPC3_ in the specific regions listed below (Walsh _et al._ 2019[<sup>14</sup>](#pmid_30696458)). ... 1. Transcripts ENST00000545968 and NM\_000256.3 ... 2. Codons 485-502 and 1248-1266 ... 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 MYBPC3 VCEP PM2 supporting rule allows activation when the variant is observed no more than once (≤1 allele) in a specified non-founder gnomAD v2.1.1 population. In the required non-cancer exome figures, the variant is observed once in Other (AC 1/AN 6,626; AF 0.000150921) and is absent from Ashkenazi Jewish (AC 0); the all-comers v2.1 records likewise show Other AC 1/AN 7,140 and Ashkenazi Jewish AC 0. This satisfies the VCEP's stated alternative, so PM2 is applied at Supporting strength.
A threshold of **≤0.00004** in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule. ... 1. Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).
PMID:20378854 explicitly identifies MYBPC3 c.1504C>T (Arg502Trp) and reports that it co-segregated with HCM in families, with a combined LOD score of 4.04. This exceeds the VCEP supporting threshold of at least 3 segregations with LOD score 0.9. The evidence is consistent with the VCEP default phenotype category of phenotype consistent with the gene but not highly specific; only genotype-positive/phenotype-positive individuals are eligible for segregation counting, and the reported combined LOD is the available quantitative segregation measure.
Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at **≥3** **segregations** (LOD score of 0.9) for **SUPPORTING**. The thresholds as proposed by Jarvik and Browning (2016)[<sup>16</sup>](#pmid_27236918) are the same at ≥3 segregations (LOD score of 0.9) for supporting. ... 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.
The VCEP permits PS4 from comparative case and population-control data when cohort denominators are available and requires the lower bound of the 95% CI around the OR to be >=5 for Supporting evidence. PMID:20378854 reports the exact variant in 34 of 1,414 unrelated HCM probands and absent in 545 healthy controls, which is a case-control comparison. Using a 0.5 continuity correction for the zero control cell, I computed OR = (34.5 x 545.5)/(1379.5 x 0.5) = 27.27, 95% CI 1.67-445.52. The lower bound 1.67 does not satisfy the VCEP Supporting requirement of >=5, so PS4 is not met. PMID:12707239 reports one R502W case without a usable control comparison, and the other reviewed variant mentions do not provide qualifying case-control counts.
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). ... 3. 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 VCEP rule applies computational evidence to this missense variant and names REVEL for protein-impact prediction and SpliceAI for predicted splice impact, without requiring a particular combination of those two predictions. REVEL is 0.64, below the VCEP PP3 threshold of >=0.70. SpliceAI reports a maximum delta score of 0.004 and therefore does not provide a deleterious splice-impact result. No named computational evidence meets the VCEP PP3 requirement.
Use of REVEL (Ioannidis _et al._ 2016[<sup>17</sup>](#pmid_27666373)) is recommended at thresholds of **≥0.70 for PP3**. ... [SpliceAI](https://spliceailookup.broadinstitute.org)[<sup>2</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
The MYBPC3 VCEP BA1 rule requires filtering allele frequency (FAF) of at least 0.001 in the gnomAD popmax subpopulation. The highest available popmax FAF is 0.000166 in gnomAD v4.1, with gnomAD v2.1 at 0.00005237; both are below 0.001, so BA1 is not met.
Allele frequency is **≥0.001** based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).
The MYBPC3 VCEP BS1 rule requires filtering allele frequency (FAF) of at least 0.0002 in the gnomAD popmax subpopulation. The highest available popmax FAF is 0.000166 in gnomAD v4.1, below 0.0002; gnomAD v2.1 is lower at 0.00005237, so BS1 is not met.
Allele frequency is **≥0.0002 for** _**MYBPC3**_ based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).
The VCEP rule applies computational evidence to this missense variant and names REVEL for protein-impact prediction and SpliceAI for predicted splice impact, without requiring a particular combination of those two predictions. REVEL is 0.64, above the VCEP BP4 threshold of <=0.40, so the named REVEL path does not support benign/no-impact evidence. SpliceAI reports no significant splice impact with a maximum delta score of 0.004, but the VCEP rule does not provide a separate SpliceAI cutoff that would override the failed REVEL threshold. BP4 is therefore not met.
Use of REVEL (Ioannidis _et al._ 2016[<sup>17</sup>](#pmid_27666373)) is recommended at thresholds of **≤0.40 for BP4**. ... [SpliceAI](https://spliceailookup.broadinstitute.org)[<sup>2</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
The MYBPC3 VCEP defines PS1 as having no cardiomyopathy-specific specifications and directs application as outlined by Richards et al. 2015. The available evidence documents the queried p.Arg502Trp variant, but does not establish a distinct nucleotide change producing the same amino-acid change with a qualifying pathogenic classification. The required same-amino-acid comparator therefore cannot be evaluated.
No cardiomyopathy specifications. Apply as outlined by Richards _et al_. 2015[<sup>6</sup>](#pmid_25741868).
No case-specific evidence documents a confirmed de novo MYBPC3 c.1504C>T event, confirmed maternity and paternity, or the recommended clinical evaluation of unaffected parents. The available literature describes affected probands and familial cosegregation, not a confirmed de novo occurrence; therefore PS2 cannot be evaluated.
Strong
The VCEP permits PM5 when a different missense variant at the same codon has a qualifying pathogenic or likely pathogenic classification under the modified guidelines without PM5, and requires comparison of the amino-acid changes. The available PM5 candidate record found no same-residue comparator, and the reviewed papers do not establish a qualifying different missense variant at codon 502. PM5 cannot therefore be assessed.
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). ... This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as _likely 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 likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change).
No case-specific evidence documents an assumed de novo occurrence without confirmation of maternity and paternity. The available literature reports familial cosegregation and does not establish an assumed de novo event in this case; therefore PM6 cannot be evaluated.
Moderate
BS3 is not assessed. The VCEP directs BS3 to the PS3 specifications, but the available variant-specific functional study reports reduced MyBP-C abundance in Arg502Trp-associated human HCM tissue rather than a normal or benign functional result. No VCEP-qualifying benign functional assay or evidence demonstrating no damaging effect was identified.
See PS3 specifications.
No case-specific non-segregation is documented. The available evidence reports cosegregation with HCM rather than affected variant-negative relatives, and provides no count of non-segregations or sufficient evaluation excluding phenocopies and alternate disease-causing variants. The VCEP requires multiple non-segregations before BS4 can be applied, so this criterion is not assessed.
Strong
The VCEP requires another variant to be pathogenic under these specifications, the queried variant to be in trans with it (or double heterozygous) in at least 2 cases, and the phenotype not to be more severe than with either variant alone. PMID:20378854 reports additional sarcomere-gene mutations in some R502W carriers and states that these carriers had more severe disease and earlier adverse cardiac events, but the extracted evidence does not establish qualifying phase and phenotype comparisons for at least 2 cases. The criterion therefore cannot be applied.
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). ... 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.
PVS1 is not applicable. The variant is NM_000256.3:c.1504C>T, NP_000247.2:p.(Arg502Trp), a missense SNV in exon 17 and not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion variant. MYBPC3 is eligible for the VCEP PVS1 framework because loss of function is an established disease mechanism, but the variant does not meet the VCEP null-variant consequence requirement. No NMD, exon-criticality, protein-length-change, or repeat-region analysis can convert this missense variant into a PVS1-eligible loss-of-function variant.
Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. ... Currently only applicable to _MYBPC3_ where LOF is an established disease mechanism.
PM3 is marked "Not Applicable" in the ClinGen Cardiomyopathy Expert Panel MYBPC3 specifications. No PM3 evidence is therefore evaluated.
Not Applicable
PM4 is not applicable. The VCEP defines this criterion for protein-length changes caused by in-frame deletions or insertions in a non-repeat region, or for stop-loss variants. This variant is a missense SNV producing p.Arg502Trp, with no deletion, insertion, stop-loss, or protein-length change. The VCEP's additional truncating-variant path is also not applicable because this variant is not truncating.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
The MYBPC3 VCEP explicitly marks PP2 as not applicable.
Not Applicable
The MYBPC3 VCEP explicitly marks PP4 as not applicable and explains that inherited cardiomyopathies have high locus heterogeneity and non-genetic etiologies. No PP4 assessment is permitted under this governing framework.
Inherited cardiomyopathies have high locus heterogeneity as well as non-genetic etiologies.
The MYBPC3 VCEP marks PP5 as not applicable for this VCEP and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Therefore, the ClinVar and author pathogenic assertions were not used as PP5.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The MYBPC3 VCEP explicitly designates BS2 as Not Applicable, so population homozygote observations cannot activate this criterion under this governing specification.
Not Applicable
The MYBPC3 VCEP explicitly marks BP1 as not applicable.
Not Applicable
BP3 is not applicable under the MYBPC3 VCEP specification, which explicitly excludes this criterion for the current gene framework. The variant's missense consequence and absence of an in-frame deletion or insertion do not alter that VCEP-level applicability decision.
Not applicable to the current genes.
The MYBPC3 VCEP marks BP5 as not applicable. Its instruction states that 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 MYBPC3 VCEP marks BP6 as not applicable for this VCEP and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Therefore, no reputable-source benign assertion was used as BP6.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The VCEP BP7 rule covers synonymous variants and intronic variants outside the splice consensus sequence (-4 and +7 outward). This variant is a missense SNV, NM_000256.3:c.1504C>T (p.Arg502Trp), in exon 17, so it lies outside BP7's stated variant scope and BP7 is not applicable before evaluating prediction evidence.
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.
Every interpreted variant in MYBPC3, mapped onto the exon structure of NM_000256.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)220 / 1,179,896 | 0.00019 |
| Remaining individuals7 / 62,462 | 0.00011 |
| African/African American3 / 74,930 | 4e-05 |
| South Asian2 / 91,094 | 2.2e-05 |
| Admixed American1 / 60,000 | 1.7e-05 |
| Remaining individuals1 / 7,140 | 0.00014 |
| European (non-Finnish)10 / 128,434 | 7.8e-05 |
| African/African American1 / 24,196 | 4.1e-05 |
| South Asian1 / 30,602 | 3.3e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000144371; MAF= 0.01444%, 233/1613896 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000186457; MAF= 0.01865%, 220/1179896 alleles, homozygotes = 0); grpmax FAF= 0.000166.
This variant is present in gnomAD v2.1 (AF= 4.6324e-05; MAF= 0.00463%, 13/280632 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000140056; MAF= 0.01401%, 1/7140 alleles, homozygotes = 0); grpmax FAF= 5.237e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 5.42947116950809e-05, 1/18418 alleles, homozygotes = 0).
The VCEP rule applies computational evidence to this missense variant and names REVEL for protein-impact prediction and SpliceAI for predicted splice impact, without requiring a particular combination of those two predictions. REVEL is 0.64, below the VCEP PP3 threshold of >=0.70. SpliceAI reports a maximum delta score of 0.004 and therefore does not provide a deleterious splice-impact result. No named computational evidence meets the VCEP PP3 requirement.
Use of REVEL (Ioannidis _et al._ 2016[<sup>17</sup>](#pmid_27666373)) is recommended at thresholds of **≥0.70 for PP3**. ... [SpliceAI](https://spliceailookup.broadinstitute.org)[<sup>2</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
The VCEP rule applies computational evidence to this missense variant and names REVEL for protein-impact prediction and SpliceAI for predicted splice impact, without requiring a particular combination of those two predictions. REVEL is 0.64, above the VCEP BP4 threshold of <=0.40, so the named REVEL path does not support benign/no-impact evidence. SpliceAI reports no significant splice impact with a maximum delta score of 0.004, but the VCEP rule does not provide a separate SpliceAI cutoff that would override the failed REVEL threshold. BP4 is therefore not met.
Use of REVEL (Ioannidis _et al._ 2016[<sup>17</sup>](#pmid_27666373)) is recommended at thresholds of **≤0.40 for BP4**. ... [SpliceAI](https://spliceailookup.broadinstitute.org)[<sup>2</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
The VCEP BP7 rule covers synonymous variants and intronic variants outside the splice consensus sequence (-4 and +7 outward). This variant is a missense SNV, NM_000256.3:c.1504C>T (p.Arg502Trp), in exon 17, so it lies outside BP7's stated variant scope and BP7 is not applicable before evaluating prediction evidence.
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.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.64. BayesDel score = 0.337461.
8 paper records listed. 3 cited in the classification.
E17 C10951T R502W 1 Missense
Location Table 3, MYBPC3 mutations, exon 17; Discussion, paragraph beginning “In each protein, amino acids may be considered ‘hot spots’ for mutations.”
Context Systematic screening of the entire coding sequences of MYBPC3 and five other genes in 197 unrelated index patients with familial or sporadic hypertrophic cardiomyopathy, using DNA single-strand conformation polymorphism analysis followed by sequencing of abnormal patterns.
Two carried previously described missense alleles Glu258Lys (sample code M10) and Arg502Trp (MA)
Location Results, paragraph 1; Figure 2B and Online Figure III/Online Table II
Context Human left ventricular septal myectomy samples from patients with hypertrophic cardiomyopathy, compared with donor heart and non-MYBPC3-mutant myectomy tissue; MYBPC3 mutation genotyping, MyBP-C immunoblotting, and quantification of MyBP-C relative to actin in myofibrillar fractions.
A variant (1504C>T) in exon 17 of MYBPC3 encoding Arg502Trp has been repeatedly recognized1, 8, 10–12, but its pathogenicity in HCM remains untested. Here we demonstrate that MYBPC3 Arg502Trp is a pathogenic missense mutation and the most common cause of HCM in a diverse Caucasian population.
Location Introduction; Results, paragraphs 1–3; Discussion
Context Genetic testing of 1,414 consecutive unrelated HCM probands; segregation analysis in MYBPC3 Arg502Trp families; comparison with 545 healthy controls; haplotype analysis in 17 of 34 variant-positive families.
BS Arg502Trp 18 MyBP-C Known
Table 1, Disease causing gene mutations identified in Australian hypertrophic cardiomyopathy probands, family BS
To illustrate the ability of the HCM array to detect mutations, we used the DNA of eight patients comprising eight different nonsynonymous nucleotide substitutions in the genes tiled on the array (p.Gly148Arg, p.Arg502Trp, and p.Arg943Stop of MYBPC3, p.Glu192Lys and p.Arg37Ser of TPM1, p.Glu87Lys of TNNT2, 50UTR of PLN, and p.Arg81His of MYL3). ... A total of 7 out of these 8 base substitutions were detected.
Results, Positive Controls and Reproducibility of Array-Based Sequencing, p. 881
The two most frequently mutated genes are MYBPC3 and MYH7.6
Sections 1.3, 1.10, and 2.3
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= 0.000144371; MAF= 0.01444%, 233/1613896 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000186457; MAF= 0.01865%, 220/1179896 alleles, homozygotes = 0); grpmax FAF= 0.000166.
This variant is present in gnomAD v2.1 (AF= 4.6324e-05; MAF= 0.00463%, 13/280632 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000140056; MAF= 0.01401%, 1/7140 alleles, homozygotes = 0); grpmax FAF= 5.237e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 5.42947116950809e-05, 1/18418 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Pathogenic (32 clinical laboratories) and as Likely pathogenic (3 clinical laboratories). (ClinVarID = 42540)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.64. BayesDel score = 0.337461.
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.