ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: 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, Mass General Brigham 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 d.broadinstitute.org; 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 2023-04-27 criteria provided, single submitter clinical testing Reported in individuals with HCM, although no segregation studies were described (Homburger et al., 2016; Walsh et al., 2017; Mazzarotto et al., 2018; Robyns et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29875424, 31513939, 27532257, 27247418, 34542152, Farne2021[article])
Invitae RCV000472710 SCV000546243 uncertain significance Hypertrophic cardiomyopathy 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1213 of the MYH7 protein (p.Val1213Met). This variant is present in population databases (rs397516182, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 29875424, 31513939). ClinVar contains an entry for this variant (Variation ID: 42958). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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 likely benign Cardiovascular phenotype 2023-03-28 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.
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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