ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1750G>A (p.Gly584Ser) (rs121913626)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000229519 SCV000059394 likely pathogenic Hypertrophic cardiomyopathy 2017-08-07 criteria provided, single submitter clinical testing The p.Gly584Ser variant in MYH7 has been reported in >5 individuals with HCM (Er dmann 2003, Zou 2013, Kapplinger 2014, Homburger 2016, LMM unpublished), and was absent large population studies. Glycine (Gly) at position 584 is highly conser ved in evolution and the change to Serine (Ser) was predicted to be pathogenic u sing a computational tool clinically validated by our laboratory. This tool's pa thogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In addition, another variant at this position, p.Gly584Arg, has been categorized a s pathogenic, supporting that changes at this position are not tolerated. Of not e, this variant lies in the head region of the protein. Missense variants in thi s region have been reported and statistically indicated to be more likely to cau se disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly584Ser variant is likely pa thogenic.
Invitae RCV000229519 SCV000284258 pathogenic Hypertrophic cardiomyopathy 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 584 of the MYH7 protein (p.Gly584Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (rs121913626, ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID:12974739, 23283745, 24510615, 26187847, 26914223). ClinVar contains an entry for this variant (Variation ID: 42862). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) and an algorithm developed specifically for the MYH7 gene (PMID: 21310275) all suggest that this missense change is likely to be deleterious, and algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing  although these predictions have not been confirmed by published functional studies. Furthermore, a different missense substitution at this codon (p.Gly584Arg) is reported to be deleterious (PMID: 24093860,8282798, 1552912, 8335820). This indicates that the glycine residue is important for MYH7 protein function. In summary, this is a missense variant that is absent from population databases, has been reported in affected individuals, and is predicted to have a deleterious effect on protein function, and is located in a residue required for proper protein function. For these reasons it has been classified as Pathogenic.
Ambry Genetics RCV000242011 SCV000319779 likely pathogenic Cardiovascular phenotype 2015-06-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,Rarity in general population databases (dbSNP, ESP, 1000 Genomes),in silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709746 SCV000840023 likely pathogenic Familial hypertrophic cardiomyopathy 1 2018-02-08 criteria provided, single submitter clinical testing The c.1750G>A (p.Gly584Ser) variant in the MYH7 gene has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) (PMID: 12974739, 23283745, 24510615, 27247418). This variant is absent from large databases of genetic variation in the general population. A different missense variant at the same position, (p.Gly584Arg), has also been reported in individuals with HCM (PMID: 24093860, 1552912, 8335820, 27532257, 27247418). The c.1750G>A (p.Gly584Ser) variant in the MYH7 gene is classified as likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000035743 SCV000917844 pathogenic Primary familial hypertrophic cardiomyopathy 2018-10-01 criteria provided, single submitter clinical testing Variant summary: MYH7 c.1750G>A (p.Gly584Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247226 control chromosomes. c.1750G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy. A variant at the same codon, p.Gly584Arg, as well as variants in adjacent codons, have been associated with HCM, suggesting the codon and motif are critical for function. Together, these data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics RCV000788633 SCV000927812 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing

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