ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3637G>A (p.Val1213Met) (rs397516182)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035851 SCV000059502 uncertain significance not specified 2017-11-02 criteria provided, single submitter clinical testing The p.Val1213Met variant in MYH7 has been reported in at least 2 individuals wit h HCM (Homburger 2016, Walsh 2017). This variant has also been identified in 5/3 4406 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma; dbSNP rs397516182). Computational prediction tools and con servation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Val1213Met variant is u ncertain. ACMG/AMP Criteria applied: PM2; PS4_Supporting.
GeneDx RCV000766449 SCV000208553 uncertain significance not provided 2018-09-25 criteria provided, single submitter clinical testing p.Val1213Met (GTG>ATG): c.3637 G>A in exon 27 of the MYH7 gene (NM_000257.2). A variant of uncertain significance has been identified in the MYH7 gene. The V1213M variant was reported once by Homburger et al. (2016) as a variant of uncertain significance in an individual with HCM. Additionally, it has been reported as a variant of uncertain significance in ClinVar by two other clinical laboratory (SCV000059502.4, SCV000280341.1; Landrum et al., 2016). Although V1213M has been observed several time in unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, segregation data was unavailable for analysis. The V1213M 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 that is conserved across species. In silico analysis suggests that this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (D1208N, Q1215H, K1216M, E1218Q) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Nevertheless, the V1213M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000472710 SCV000546243 uncertain significance Hypertrophic cardiomyopathy 2019-10-18 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1213 of the MYH7 protein (p.Val1213Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 29875424). ClinVar contains an entry for this variant (Variation ID: 42958). 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 C0"). 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.
Ambry Genetics RCV000617231 SCV000736373 uncertain significance Cardiovascular phenotype 2016-11-10 criteria provided, single submitter clinical testing Insufficient evidence
Center for Human Genetics,University of Leuven RCV000472710 SCV000886836 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000035851 SCV000280341 uncertain significance not specified 2014-07-07 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. p.Val1213Met In the MYH7 gene. See report below. The variant is novel. This is a conservative amino acid change. The Grantham score is 21. The valine at codon 1213 is conserved across species, as are neighboring amino acids. I could find no other variants reported in association with disease at this codon. There is one nearby variant reported in association with disease (p.Glu1218Gln). In total the variant has not been seen in ~6500 individuals from publicly available population datasets. There is no variation at codon 1213 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6500 Caucasian and African American individuals (as of April 29th, 2014). The variant is listed in dbSNP, however there is a note that the rsID is invalid and I cannot access any data from that listing (rs397516182).

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