The MYBPC3 NM_000256.3:c.2373dup (NP_000247.2:p.(Trp792ValfsTer41)) frameshift variant has not previously been reported in somatic cancers (COSMIC). This variant is predicted to result in an absent or disrupted protein product. Experimental evidence: Cardiac studies of seven c.2373dupG carriers showed absent truncated protein, 33% lower full-length cMyBP-C, and reduced cardiomyocyte force. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A 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.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, very strong: the exon 24 frameshift truncates MYBPC3 at p.792, well before the VCEP's p.1254 NMD-escape boundary.
Met at Supporting: cardiac studies of seven c.2373dupG carriers showed absent truncated protein, 33% lower full-length cMyBP-C, and reduced cardiomyocyte force.
Met at Supporting: gnomAD v2.1 non-cancer exomes show 0 alleles in both Other and Ashkenazi Jewish non-founder populations, satisfying the VCEP PM2 path.
Met at Supporting: SpliceAI predicts a possible splice impact with maximum delta score 0.351, including DS_DG=0.351.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PVS1 (very strong) plus PS3, PM2, and PP3 (supporting) satisfy the MYBPC3 VCEP's Rule4.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 42 / 1,563,840 alleles. Recorded AF 2.6857e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 1.744e-05; MAF= 0.00174%, 3/172018 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.27704e-05; MAF= 0.00428%, 3/70142 alleles, homozygotes = 0); grpmax FAF= 1.136e-05.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.351. Refer to the recorded PP3/BP4 rationale for interpretation.
36 Pathogenic · 1 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 · 2 not met · 7 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 is met at very strong strength for the MYBPC3 exon 24 frameshift truncating at p.792, before the VCEP's p.1254 NMD-escape boundary.
PM4 and BP3 are not applicable under the MYBPC3 VCEP specification.
All five requested criteria are not applicable under the MYBPC3 VCEP: c.2373dup is a frameshift, PM1 is restricted to specified missense regions, PM5 requires a same-codon missense comparator, and PP2/BP1 are explicitly Not Applicable.
Only PS4, PP4, PP5, BP5, and BP6 were adjudicated.
The VCEP-specific applicability entries make PP4, PP5, BP5, and BP6 Not Applicable.
PS4 remains not assessed because the available affected-carrier reports do not provide the eligible case-control denominators required to calculate an OR and 95% CI under the MYBPC3 VCEP.
No criteria match.
NM_000256.3:c.2373dup is a frameshift variant predicted to produce NP_000247.2:p.(Trp792ValfsTer41) in exon 24 of MYBPC3. The VCEP permits PVS1 for MYBPC3 because loss of function is an established disease mechanism. The predicted premature termination occurs at p.792, before the VCEP's p.1254 boundary, so the VCEP's NMD-escape caution does not apply; the variant is therefore assessed at full, un-downgraded PVS1 strength. Cardiac-tissue data for the exact c.2373dupG allele show reduced mutant transcript, absent truncated protein, and reduced full-length cMyBP-C, consistent with loss of function.
Currently only applicable to _MYBPC3_ where LOF is an established disease mechanism. ... Factors to consider when assessing the consequences of putative LOF variants in the _MYBPC3_ gene: ... 1. Codon p.1254 is located 50 nucleotides upstream of the most 3' exon-exon junction (exon 33:34) in _MYBPC3._ As such, nonsense variants introducing a premature termination codon after this point may escape nonsense mediated decay (NMD) and consequently not result in protein haploinsufficiency (Nagy & Maquat 1998[<sup>3</sup>](#pmid_9644970)).
PS3 is met at Supporting strength. The variant-specific study of seven MYBPC3 c.2373dupG carriers used cardiac left-ventricular septal biopsies and demonstrated abnormal transcript processing, markedly reduced mutant mRNA, absence of detectable truncated cMyBP-C, approximately 33% reduction of full-length cMyBP-C, and reduced maximal cardiomyocyte force with increased calcium sensitivity. These findings are biologically relevant and directly support a damaging loss-of-function effect. The VCEP states that individual in vitro cardiomyopathy assays are unlikely to support PS3 above Supporting because no validated gold-standard assay reliably predicts the clinical phenotype; the evidence does not satisfy the VCEP's separate Strong splicing-assay requirements, including a clearly documented reproducible splice product comparable to wild type, control comparison, and Sanger confirmation.
_**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 MYBPC3 VCEP applies PM2 at Supporting when the population and disease-model assumptions are satisfied and the variant is absent or sufficiently rare in the specified population. Its alternative gnomAD v2.1.1 path is met: the variant is absent from the Other population (0 alleles) and Ashkenazi Jewish population (0 alleles), both among the VCEP's named non-founder populations. The governing rule also gives the equivalent upper-bound threshold of ≤0.00004 and supports the specified gnomAD v2.1.1 non-founder-population absence path. The gnomAD v2.1 non-cancer exomes record contains 3/165,494 alleles overall, no homozygotes, 0 alleles in Other, and 0 alleles in Ashkenazi Jewish; because the VCEP rule specifically names gnomAD v2.1.1 and this case provides the non-cancer exome subset, that subset is used for the PM2 assessment.
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>15</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. ... 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).
The MYBPC3 VCEP permits PP3 at Supporting strength for computational evidence and specifically recommends SpliceAI for predicted splice impacts. This coding frameshift is within exon 24, and the available SpliceAI result predicts a possible splice impact with a maximum delta score of 0.351, including DS_DG=0.351. REVEL is not applicable to this non-SNV frameshift and was not used. The SpliceAI result is used for PP3 only and is not reused for BP4 or BP7.
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>17</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>2</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
The MYBPC3 VCEP requires a filtering allele frequency (FAF) of at least 0.001 in the gnomAD popmax subpopulation for BA1. The highest available all-comers popmax FAF is 2.642e-05 in gnomAD v4.1, below 0.001; gnomAD v2.1 all-comers also has a popmax FAF of 1.136e-05. The VCEP does not specify a non-cancer restriction for BA1, so the all-comers FAF values are the applicable default.
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 requires a gnomAD popmax FAF of at least 0.0002 for BS1. The highest available all-comers popmax FAF is 2.642e-05 in gnomAD v4.1, which is below 0.0002; gnomAD v2.1 all-comers has a lower popmax FAF of 1.136e-05. The VCEP does not specify a non-cancer restriction for BS1, so the all-comers FAF values are the applicable default.
Allele frequency is **≥0.0002 for** _**MYBPC3**_ based on the **filtering allele frequency (FAF)** in **gnomAD** in the subpopulation with the highest frequency (popmax).
No case-specific evidence documents a de novo occurrence of NM_000256.3:c.2373dup, including confirmed maternity and paternity, parental genotypes, or thorough parental cardiac evaluation. The available literature describes an inherited multigeneration/founder context rather than a confirmed de novo proband. The VCEP rule therefore cannot be evaluated for this case.
Strong
The MYBPC3 VCEP requires a case-control comparison with available denominators and, for supporting PS4, the lower bound of the 95% CI around the odds ratio must be >=5. The available literature includes affected Dutch index patients carrying 2373insG, but no eligible unaffected/population-control count or complete matched case-control table is available, so an OR and 95% CI cannot be calculated. The literature_pass packet's AI-classified papers were checked: none was classified as PS4; the 10736283 paper was classified for PS3/PP1, not PS4. The available case-series evidence therefore does not establish PS4 at any strength.
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**
No case-specific evidence documents an assumed de novo occurrence of NM_000256.3:c.2373dup in a proband with sufficient phenotype characterization and parental information. The available evidence concerns an inherited multigeneration/founder occurrence, and the required phenotype-specific case count cannot be established. The VCEP rule therefore cannot be evaluated.
Moderate
Moolman et al. reports a multigeneration family with affected gene carriers and cosegregation of the MYBPC3 mutation with hypertrophic cardiomyopathy, but the available record does not provide the number of genotype-positive/phenotype-positive individuals, clinically confirmed individual-level phenotypes, or a segregation count. The VCEP Supporting threshold requires at least 3 segregations, so PP1 cannot be assigned from the available detail.
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. Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis. Important considerations include: 1. Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant. If linkage disequilibrium is a concern, consider downgrading strength of segregation. 2. Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below). 3. Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 4. Caution is needed when distantly related (≥3<sup>rd</sup> degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).
BS3 is not assessed. The available functional evidence is damaging rather than benign: the variant-specific cardiac study showed abnormal transcript processing, reduced cMyBP-C expression, and impaired cardiomyocyte contractile force. No validated assay showing no damaging effect on MYBPC3 protein function or splicing was identified, so the VCEP's PS3/BS3 functional specifications do not provide a basis for applying BS3.
See PS3 specifications.
No case-specific non-segregation is documented. The available family evidence reports affected gene carriers and incomplete penetrance but does not identify affected variant-negative relatives, provide individual-level genotype/phenotype pairs, or establish that any non-segregation is unlikely to reflect a phenocopy or an alternate disease-causing variant. The VCEP requires at least 2 qualifying non-segregations, so BS4 cannot be assessed.
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. 1. The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. 2. Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’. 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). Careful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.
The VCEP BP2 rule requires another variant to be pathogenic under these specifications, documented cis/trans status, and observation in trans or as a double heterozygote in at least two cases with no phenotype more severe than either variant in isolation. The available evidence documents affected carriers and functional effects for c.2373dupG, but does not document a qualifying second pathogenic variant, phase, or at least two qualifying cases; therefore BP2 cannot be assessed.
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.
The VCEP directs PS1 to be applied as originally described, but NM_000256.3:c.2373dup is predicted to encode p.(Trp792ValfsTer41), a frameshift rather than an amino-acid substitution. The same-amino-acid-change criterion therefore does not apply.
No cardiomyopathy specifications. Apply as outlined by Richards _et al_. 2015[<sup>6</sup>](#pmid_25741868).
The MYBPC3 VCEP limits PM1 to missense variants in codons 485-502 and 1248-1266 on the specified transcripts. This case variant is a frameshift, not a missense variant, so PM1 does not apply.
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
PM3 is not applicable under the ClinGen Cardiomyopathy Expert Panel MYBPC3 Version 1.0 specifications. Therefore, phase, affected-proband observations, and inheritance-mode evidence cannot activate PM3 under this governing framework.
Not Applicable
The VCEP's PM4 rule is defined for protein length changes from in-frame deletions/insertions in a non-repeat region or stop-loss variants. NM_000256.3:c.2373dup is a frameshift, not an in-frame insertion/deletion or stop-loss variant. The VCEP additionally describes truncating-variant use of PM4 only where PVS1 is not applicable; PVS1 is applicable and met here.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. ... 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 VCEP PM5 rule requires a different missense variant at the same codon classified as pathogenic or likely pathogenic under the modified guidelines. NM_000256.3:c.2373dup is a frameshift, not a missense variant, so PM5 does not apply.
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 MYBPC3 VCEP explicitly marks PP2 as not applicable.
Not Applicable
The MYBPC3 VCEP marks PP4 as Not Applicable. No phenotype-specific PP4 evidence can be applied under this governing specification.
Not Applicable
The MYBPC3 VCEP marks PP5 as Not Applicable. Although the literature packet contains a case-series classifier reading that reports c.2373dup as pathogenic in affected neonates, that report cannot activate PP5 under this VCEP.
Not Applicable
The MYBPC3 VCEP marks BS2 as Not Applicable. Therefore, the absence of homozygotes in gnomAD (0 in the available datasets) is not used to apply BS2.
Not Applicable
The MYBPC3 VCEP explicitly marks BP1 as not applicable.
Not Applicable
The VCEP explicitly marks BP3 as not applicable to the current genes. Independently, the variant is a frameshift rather than the in-frame deletion/insertion described by the BP3 rule.
Not applicable to the current genes. ... In frame-deletions/insertions in a repetitive region without a known function.
BP4 is not applicable to this variant because NM_000256.3:c.2373dup is a frameshift variant. A no-impact splice prediction would not negate the truncating protein consequence; therefore the available SpliceAI prediction is not evidence for BP4 and is not reused here.
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>17</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>2</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
The MYBPC3 VCEP marks BP5 as Not Applicable. No BP5 assessment may be substituted from generic ACMG/AMP rules or other frameworks.
Not Applicable
The MYBPC3 VCEP marks BP6 as Not Applicable. No benign assertion from a laboratory or database may activate BP6 under this VCEP.
Not Applicable
BP7 is limited by the VCEP rule to synonymous variants and intronic variants outside the splice consensus sequence. NM_000256.3:c.2373dup is a coding frameshift in exon 24, so it lies outside BP7 scope regardless of its SpliceAI result or nucleotide conservation.
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>6</sup>](#pmid_25741868).
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)41 / 1,154,296 | 3.6e-05 |
| Remaining individuals1 / 60,666 | 1.6e-05 |
| European (non-Finnish)3 / 70,142 | 4.3e-05 |
This variant is present in gnomAD v4.1 (AF= 2.6857e-05; MAF= 0.00269%, 42/1563840 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.55195e-05; MAF= 0.00355%, 41/1154296 alleles, homozygotes = 0); grpmax FAF= 2.642e-05.
This variant is present in gnomAD v2.1 (AF= 1.744e-05; MAF= 0.00174%, 3/172018 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.27704e-05; MAF= 0.00428%, 3/70142 alleles, homozygotes = 0); grpmax FAF= 1.136e-05.
Not available in gnomAD-Canada v1.0.
The MYBPC3 VCEP permits PP3 at Supporting strength for computational evidence and specifically recommends SpliceAI for predicted splice impacts. This coding frameshift is within exon 24, and the available SpliceAI result predicts a possible splice impact with a maximum delta score of 0.351, including DS_DG=0.351. REVEL is not applicable to this non-SNV frameshift and was not used. The SpliceAI result is used for PP3 only and is not reused for BP4 or BP7.
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>17</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>2</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
BP4 is not applicable to this variant because NM_000256.3:c.2373dup is a frameshift variant. A no-impact splice prediction would not negate the truncating protein consequence; therefore the available SpliceAI prediction is not evidence for BP4 and is not reused here.
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>17</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>2</sup>](#pmid_30661751) is recommended for evaluation of predicted splice impacts.
BP7 is limited by the VCEP rule to synonymous variants and intronic variants outside the splice consensus sequence. NM_000256.3:c.2373dup is a coding frameshift in exon 24, so it lies outside BP7 scope regardless of its SpliceAI result or nucleotide conservation.
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>6</sup>](#pmid_25741868).
SpliceAI predicts possible splice impact for this variant (max delta score = 0.35).
9 paper records listed. 1 cited in the classification.
The c.2373dupG mutation was expected to induce a cryptic donor splice site in exon 24 and the skipping of 40 nucleotides.
Location Methods, Cardiac Biopsies; Results, Reduced Mutant cMyBP-C mRNA Level in FHCM Ventricular Tissue; Results, Reduced cMyBP-C Protein Level in FHCM Ventricular Tissue; Depressed Force Development
Context Cardiac left-ventricular septal biopsies from seven MYBPC3 c.2373dupG carriers with hypertrophic obstructive cardiomyopathy; allele-specific RT-PCR, immunoblotting, protein analysis, and force-pCa measurements in permeabilized cardiomyocytes.
History and clinical status (examination, ECG, and echocardiography) were assessed in 49 members of a multigeneration family.
Abstract
We initially screened 22 Dutch index patients for mutations in the MYBPC3 gene, which revealed four different mutations in 14 patients. The 2373insG mutation was identified in 10 appa
Abstract
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= 2.6857e-05; MAF= 0.00269%, 42/1563840 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.55195e-05; MAF= 0.00355%, 41/1154296 alleles, homozygotes = 0); grpmax FAF= 2.642e-05.
This variant is present in gnomAD v2.1 (AF= 1.744e-05; MAF= 0.00174%, 3/172018 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.27704e-05; MAF= 0.00428%, 3/70142 alleles, homozygotes = 0); grpmax FAF= 1.136e-05.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (36 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 42619)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.35).
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.