ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5329G>A (p.Ala1777Thr) (rs200939753)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000465931 SCV000564458 uncertain significance Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.5329G>A (p.Ala1777Thr) variant in MYH7 has been reported in 3 individuals with hypertrophic cardiomyopathy (PS4_Supporting; PMID:27532257; PMID:12707239). This variant has been identified in 4/66738 European chromosomes (PM2; http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM2; PP3; PS4_ Supporting
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171839 SCV000050863 likely pathogenic Primary familial hypertrophic cardiomyopathy 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154298 SCV000203957 uncertain significance not specified 2017-08-29 criteria provided, single submitter clinical testing The p.Ala1777Thr variant in MYH7 has been reported in 6 individuals with HCM, 1 individual with DCM, 1 individual with myopathy, and 1 individual with RCM who c arried a second pathogenic MYH7 variant (Richard 2003, Ng 2013, Walsh 2017, Evil a 2016, Bos 2014, Hertz 2014, LMM data). The p.Ala1777Thr variant has also been identified in 17/126714 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200939753). Computational pre diction tools and conservation analysis do not provide strong support for or aga inst an impact to the protein. Furthermore, in vitro functional studies suggest that the variant may not impact protein function (Wallefeld 2010); however, thes e types of assays may not accurately represent biological function. In summary, given the broad phenotypic spectrum associated with this variant and the presenc e of conflicting data, the clinical significance of the p.Ala1777Thr variant is uncertain.
GeneDx RCV000154298 SCV000208630 uncertain significance not specified 2017-05-17 criteria provided, single submitter clinical testing While the A1777T variant in the MYH7 gene has been published in association with HCM (Richard et al., 2003), it has also been reported in one patient with Brugada syndrome and in one patient with camptocormia but a normal cardiac evaluation (Hertz et al., 2015; Chanson et al., 2016). The A1777T variant is also reported in one individual from a cohort that underwent exome sequencing and in which individuals were not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death (Ng et al., 2013). The A1777T 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. In addition, this substitution occurs at a position that is conserved across species. Nonetheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, the A1777T variant is observed in 4/66738 alleles from individuals of European Non-Finnish ancestry in the ExAC dataset (Lek et al., 2016; McVean et al., 2012; Exome Variant Server). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Blueprint Genetics RCV000171839 SCV000264099 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-04-24 criteria provided, single submitter clinical testing
Invitae RCV000465931 SCV000546239 uncertain significance Hypertrophic cardiomyopathy 2019-10-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1777 of the MYH7 protein (p.Ala1777Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs200939753, ExAC 0.01%). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 177697). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000620826 SCV000739971 uncertain significance Cardiovascular phenotype 2016-06-17 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV001111830 SCV001269431 uncertain significance Familial hypertrophic cardiomyopathy 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color RCV001183990 SCV001349854 uncertain significance Cardiomyopathy 2020-02-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000154298 SCV001360967 uncertain significance not specified 2019-03-04 criteria provided, single submitter clinical testing Variant summary: MYH7 c.5329G>A (p.Ala1777Thr) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 277234 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in MYH7 causing Cardiomyopathy (0.00013 vs 0.0013), allowing no conclusion about variant significance. c.5329G>A has been reported in the literature in individuals affected with hypertrophic- (HCM), dilated (DCM) and restrictive (RCM) cardiomyopathy (Richard 2003, Ng 2013, Bos 2014, Homburger 2016, Walsh 2017, Kelly 2018), and also in one patient with Brugada syndrome (Hertz 2014). These reports do 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (five classifying the variant as VUS, and one as likely pathogenic). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Neurology, University Hospital of Strasbourg RCV000186557 SCV000240099 pathogenic Idiopathic camptocormia 2014-01-01 no assertion criteria provided literature only

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