ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1876G>A (p.Gly626Arg) (rs876661370)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244710 SCV000317827 uncertain significance Cardiovascular phenotype 2012-11-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000535668 SCV000623653 uncertain significance Hypertrophic cardiomyopathy 2017-06-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 626 of the MYH7 protein (p.Gly626Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 235027). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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, this variant has uncertain impact on MYH7 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223917 SCV000280306 uncertain significance not specified 2011-08-05 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gly626Arg (G626R; c.1876 G>A) in the MYH7 gene This variant appears to be completely novel, and has not been previously reported as a disease-causing mutation or as a benign polymorphism according to searches of PubMed and Google. This is a non-conservative amino acid change from a nonpolar glycine to a positively-charged, basic arginine with a much bigger sidechain. It has a Grantham score of 125. The glycine at codon 626 is highly conserved across 35/37 vertebrate species examined (it is an alanine in microbat and a serine in stickleback). Ambry reports that in silico analysis with PolyPhen-2 (humVAR) predicts the variant to be “benign” with a score of 0.419; SIFT predicts it to be “deleterious” with a score of 0.040. In total this specific variant has not been seen in ~7500 published controls and individuals from publicly available population datasets, including ~2446 individuals ethnicity-matched to our African-American patient. It is not present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 1/7/2013). It is not present in dbSNP or in 1000 genomes. (1000 genomes phase 1 is made up of 1092 individuals of various races, 246 of them with African or African-American ancestry).

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