Submissions for variant NM_002471.4(MYH6):c.2401A>G (p.Ile801Val)

gnomAD frequency: 0.00028  dbSNP: rs75487328

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037454	SCV000061112	uncertain significance	not specified	2012-04-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ile801Val varia nt (MYH6) has not been reported in the literature nor previously identified by o ur laboratory. Computational analyses (biochemical amino acid properties, conser vation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ile801Val variant may n ot impact the protein, though this information is not predictive enough to rule out pathogenicity. Of note, the chicken carries a valine (Val) at this position, suggesting that this change may be tolerated. Although this data supports that this variant may be benign, additional studies are needed to fully assess its cl inical significance.
Ambry Genetics	RCV000618074	SCV000739998	likely benign	Cardiovascular phenotype	2016-08-17	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256734	SCV001433140	uncertain significance	Dilated cardiomyopathy 1A	2019-12-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001365449	SCV001561721	uncertain significance	Hypertrophic cardiomyopathy 14	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 801 of the MYH6 protein (p.Ile801Val). This variant is present in population databases (rs75487328, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28082330). ClinVar contains an entry for this variant (Variation ID: 44463). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037454	SCV001572433	benign	not specified	2021-04-15	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.2401A>G (p.Ile801Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251450 control chromosomes, predominantly at a frequency of 0.0004 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 16-fold the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.2401A>G has been reported in the literature in at least one individual affected with Cardiomyopathy without strong evidence for causality (e.g. Walsh_2017). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as likely benign, and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.