Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
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, |
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 | 2021-09-30 | 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 has been detected in an individual referred for dilated cardiomyopathy genetic testing, and in a subject with congenital heart disease who also carried a second missense alteration in MYH6 (Jin SC et al. Nat. Genet., 2017 Nov;49:1593-1601; Marschall C et al. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Gene |
RCV000766505 | SCV000582067 | uncertain significance | not provided | 2018-08-17 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the MYH6 gene. The G585S variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G585S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. |
Invitae | RCV000689618 | SCV000817277 | uncertain significance | Hypertrophic cardiomyopathy 14 | 2024-01-22 | 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). 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 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, |
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, |
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, |
RCV003149587 | SCV003838738 | uncertain significance | Cardiomyopathy | 2021-07-05 | criteria provided, single submitter | clinical testing |