Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001727522 | SCV001976473 | uncertain significance | Hypertrophic cardiomyopathy | 2021-08-25 | reviewed by expert panel | curation | The c.707T>C (p.Val236Ala) variant in MYH7 has been identified in 2 individuals with HCM (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers comm; LMM pers comm). This variant has also been observed in relatives with non-compaction cardiomyopathy, though this is considered insufficient to apply PP1. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to a lack of 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): PS4_Supporting; PM2, PM1. |
Laboratory for Molecular Medicine, |
RCV000035992 | SCV000059644 | uncertain significance | not specified | 2019-07-17 | criteria provided, single submitter | clinical testing | The p.Val236Ala variant in MYH7 has been identified in 1 individual with HCM (LMM data) and was absent from large population studies. It has been reportedi n ClinVar (Variation ID #43097). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM1, PM2. |
Gene |
RCV000767174 | SCV000279743 | uncertain significance | not provided | 2016-01-04 | criteria provided, single submitter | clinical testing | The V236A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been reported as a variant of uncertain significance in the ClinVar database by an outside laboratory (Landrum et al., 2014). The V236A 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. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. However, the V236A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. |
Blueprint Genetics | RCV000767174 | SCV000927894 | likely pathogenic | not provided | 2018-08-30 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001727522 | SCV003442293 | uncertain significance | Hypertrophic cardiomyopathy | 2022-08-27 | 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. 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). 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 43097). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 27532257, 33673806). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 236 of the MYH7 protein (p.Val236Ala). |