ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.1753G>A (p.Gly585Ser) (rs150415679)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250070 SCV000318530 uncertain significance Cardiovascular phenotype 2017-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx 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.
Illumina Clinical Services Laboratory,Illumina RCV000405421 SCV000385738 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000304935 SCV000385739 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000343459 SCV000385740 uncertain significance Atrial septal defect 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000030305 SCV000052972 likely benign Cardiomyopathy 2015-10-02 no assertion criteria provided clinical testing
Invitae RCV000689618 SCV000817277 uncertain significance Familial hypertrophic cardiomyopathy 14 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 585 of the MYH6 protein (p.Gly585Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs150415679, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with congenital heart defects who also carried another variant in MYH6 (PMID: 28991257). ClinVar contains an entry for this variant (Variation ID: 36627). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare 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.

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