Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000706236 | SCV002041490 | uncertain significance | Hypertrophic cardiomyopathy | 2021-11-19 | reviewed by expert panel | curation | The NM_000257.4(MYH7):c.511A>C (p.Asn171His) variant has been identified in 1 individual with HCM (GeneDx pers. comm.), however, this data is insufficient to apply the PS4 criterion. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3. |
Gene |
RCV000158740 | SCV000208675 | likely pathogenic | not provided | 2014-03-09 | criteria provided, single submitter | clinical testing | A N171H variant that is likely pathogenic was identified in the MYH7 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The N171H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N171H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is highly conserved through vertebrates. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in nearby residues (R169G, E170K, T177I, G178R) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in HCM panel(s). |
Invitae | RCV000706236 | SCV000835275 | uncertain significance | Hypertrophic cardiomyopathy | 2022-03-25 | criteria provided, single submitter | clinical testing | 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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 181310). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 171 of the MYH7 protein (p.Asn171His). |