Submissions for variant NM_002471.4(MYH6):c.3199A>G (p.Ser1067Gly)

gnomAD frequency: 0.00027  dbSNP: rs145508517

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172562	SCV000054813	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037470	SCV000061128	uncertain significance	not specified	2017-02-22	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ser1067Gly va riant in MYH6 has been identified by our laboratory in 1 Hispanic individual wit h HCM, but did NOT segregate with disease in 1 affected relative. This variant w as identified in 0.1% (11/10406) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145508517). Computat ional prediction tools and conservation analysis do not provide strong support f or or against an impact to the protein. This variant was identified in ClinVar ( Variant ID:44477). In summary, while the clinical significance of the p.Ser1067G ly variant is uncertain, its frequency and non-segregation suggests that it is m ore likely to be benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037470	SCV000917834	likely benign	not specified	2018-05-29	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.3199A>G (p.Ser1067Gly) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant frequency in the gnomAD database was 0.000097, but was observed predominantly in the African subpopulation at a frequency of 0.00099. This frequency within African control individuals in the gnomAD database is approximately 40 fold above 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 African origin. c.3199A>G has been reported in the literature, however, 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as uncertain significance, although the summary evidence provided by one of them suggests a benign etiology. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088527	SCV001006023	likely benign	Hypertrophic cardiomyopathy 14	2024-09-14	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000172562	SCV001715059	uncertain significance	not provided	2019-04-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000172562	SCV001768154	uncertain significance	not provided	2024-04-19	criteria provided, single submitter	clinical testing	Has not been previously published in association with an MYH6-related disorder to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23861362)
Ambry Genetics	RCV002321509	SCV002609115	likely benign	Cardiovascular phenotype	2019-05-31	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.