Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV001195109 | SCV000203881 | likely pathogenic | Hypertrophic cardiomyopathy | 2019-10-09 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Color Diagnostics, |
RCV001183967 | SCV001349826 | uncertain significance | Cardiomyopathy | 2018-12-12 | criteria provided, single submitter | clinical testing | Variant of Uncertain Significance due to insufficient evidence: This variant is located in the myosin head/motor (S1) domain of the MYH7 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in compound heterozygosity with a pathogenic variant p.Arg663His in an individual affected with childhood-onset cardiac hypertrophy (PMID: 18403758). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000154226 | SCV001360970 | uncertain significance | not specified | 2019-08-13 | criteria provided, single submitter | clinical testing | Variant summary: MYH7 c.2287G>A (p.Val763Met) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251358 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2287G>A, has been reported in the literature in individuals affected with Cardiomyopathy (Morita_2008, Adler_2016, Walsh_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrence with another pathogenic variant have been reported ( MYH7 c.1988G>A, p.Arg663His) (Morita_2008), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Invitae | RCV001195109 | SCV001379734 | uncertain significance | Hypertrophic cardiomyopathy | 2022-03-20 | criteria provided, single submitter | clinical testing | This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 177642). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 18403758, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 763 of the MYH7 protein (p.Val763Met). |
| Ambry Genetics | RCV002444635 | SCV002735530 | uncertain significance | Cardiovascular phenotype | 2021-10-28 | criteria provided, single submitter | clinical testing | The p.V763M variant (also known as c.2287G>A) is located in coding exon 19 of the MYH7 gene. The valine at codon 763 is replaced by methionine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 19. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been detected in a pediatric hypertrophic cardiomyopathy patient who also carried a pathogenic mutation in MYH7 (Morita H et al. N. Engl. J. Med. 2008;358:1899-908). This variant has also been reported in an HCM cohort and in an arrhythmia cohort; however, clinical details were limited (Adler A et al. Circ Arrhythm Electrophysiol. 2016;9:e003440; Walsh R et al. Genet. Med. 2017;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |