Submissions for variant NM_002471.4(MYH6):c.3787G>A (p.Val1263Met)

gnomAD frequency: 0.00006  dbSNP: rs375819633

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222113	SCV000270451	likely benign	not specified	2015-01-28	criteria provided, single submitter	clinical testing	p.Val1263Met in exon 27 of MYH6: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, >10 mammals have a methionine (Met) at this position despite high nearby a mino acid conservation. In addition, this variant has been identified in 3/10579 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs375819633).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704700	SCV000833659	uncertain significance	Hypertrophic cardiomyopathy 14	2024-07-11	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 1263 of the MYH6 protein (p.Val1263Met). This variant is present in population databases (rs375819633, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 227590). 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 not expected to disrupt MYH6 protein function with a negative predictive value of 80%. 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	RCV002347826	SCV002622574	likely benign	Cardiovascular phenotype	2024-06-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
PreventionGenetics, part of Exact Sciences	RCV004529368	SCV004110784	uncertain significance	MYH6-related disorder	2022-11-19	criteria provided, single submitter	clinical testing	The MYH6 c.3787G>A variant is predicted to result in the amino acid substitution p.Val1263Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23858874-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneDx	RCV004812309	SCV005437673	uncertain significance	not provided	2024-06-16	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge