Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000473946 | SCV000546489 | likely benign | Hypertrophic cardiomyopathy | 2024-01-31 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000223809 | SCV000919803 | likely benign | not specified | 2021-03-11 | criteria provided, single submitter | clinical testing | Variant summary: MYBPC3 c.94G>A (p.Glu32Lys) results in a conservative amino acid change located in the Immunoglobulin I-set (IPR013098) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 272046 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.94G>A has been reported in the literature (Claes_2016). This report however, does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Co-occurrence with another likely pathogenic variant has been reported (TTN c.43732C>T, p.Gln14578Ter) in our internal database, providing supporting evidence for a benign role. Two other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. |
| Color Diagnostics, |
RCV001187346 | SCV001354117 | uncertain significance | Cardiomyopathy | 2023-11-15 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with lysine at codon 32 of the MYBPC3 protein. Computational prediction tool indicates that this variant has an uncertain impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy in one family (PMID: 26497160). Two of them also carried a pathogenic variant in the MYL2 gene that could explain the observed phenotype. This variant has been identified in 43/272046 chromosomes (40/34794 Latino chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV002372031 | SCV002688230 | likely benign | Cardiovascular phenotype | 2022-10-25 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000223809 | SCV000280288 | uncertain significance | not specified | 2014-07-05 | no assertion criteria provided | clinical testing | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Glu32Lys Based on the data reviewed below we consider this variant a variant of uncertain significance. The variant is novel. We could find no reports of the variant in association with disease (as of July 29, 2015). The variant is located in exon 2 of the MYBPC3 gene. It results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The glutamic acid at codon 32 is conserved across species, as are neighboring amino acids. Variant in nearby residues have been reported in association with cardiomyopathy (Ala27Val; Val28Met; Thr33Ala; Glu34Asp) (Stenson P et al., 2009), supporting the functional importance of this region. The variant was reported online in 7 of 44,769 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 29th, 2015). Specifically, the variant was observed in 6 of 4281 Latino individuals (MAF 0.07%) and 1 of 3350 African indidiuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. |