Submissions for variant NM_002471.4(MYH6):c.1753G>A (p.Gly585Ser)

gnomAD frequency: 0.00014  dbSNP: rs150415679

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037446	SCV000052972	uncertain significance	not specified	2020-08-17	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.1753G>A (p.Gly585Ser) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251460 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1753G>A has been reported in the literature in at least one individual affected with congenital heart disease (CHD). This report however, 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. Three other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037446	SCV000061104	uncertain significance	not specified	2014-03-11	criteria provided, single submitter	clinical testing	The Gly585Ser variant in MYH6 has now been identified by our laboratory in one C aucasian adult with RCM, who carried a pathogenic variant in another RCM associa ted gene, and one individual with ischemic cardiomyopathy and congestive heart f ailure. This variant has also been identified in 3/8600 of European American chr omosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /; dbSNP rs150415679). Computational prediction tools and conservation analyses suggest that the Gly585Ser variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. In summary, additional i nformation is needed to fully assess its clinical significance.
Ambry Genetics	RCV000250070	SCV000318530	uncertain significance	Cardiovascular phenotype	2024-12-03	criteria provided, single submitter	clinical testing	The p.G585S variant (also known as c.1753G>A), located in coding exon 13 of the MYH6 gene, results from a G to A substitution at nucleotide position 1753. The glycine at codon 585 is replaced by serine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with congenital heart disease; in one case, a second MYH6 variant was also identified (Jin SC et al. Nat. Genet., 2017 Nov;49:1593-1601; Zhu W et al. Genes (Basel). 2022 Apr;13(4)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000766505	SCV000582067	uncertain significance	not provided	2024-09-05	criteria provided, single submitter	clinical testing	Identified in a patient with DCM and in a patient with coarctation of aorta and aortic arch hypoplasia/interrupted aortic arch (PMID: 35456442, 31737537); Reported in trans with another missense variant in the MYH6 gene in one proband diagnosed with Shone complex, a congenital heart disease involving multiple left-sided obstructive cardiac anomalies; however, additional variants were also identified in other genes including three heterozygous loss-of-function variants and a de novo synonymous variant (PMID: 28991257); 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: 34426522, 31737537, 35456442, 28991257)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689618	SCV000817277	uncertain significance	Hypertrophic cardiomyopathy 14	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 585 of the MYH6 protein (p.Gly585Ser). This variant is present in population databases (rs150415679, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of MYH6-related conditions (PMID: 28991257, 31737537, 35456442). ClinVar contains an entry for this variant (Variation ID: 36627). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH6 protein function with a positive 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256810	SCV001433265	uncertain significance	Hypertrophic cardiomyopathy 1	2019-10-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001334049	SCV001526786	uncertain significance	Atrial septal defect 3	2018-12-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV002490421	SCV002782508	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2022-04-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149587	SCV003838738	uncertain significance	Cardiomyopathy	2021-07-05	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000766505	SCV005199375	uncertain significance	not provided	2023-10-09	criteria provided, single submitter	clinical testing