ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser) (rs397516179)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244617 SCV000320054 uncertain significance Cardiovascular phenotype 2017-12-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Center for Human Genetics,University of Leuven RCV000475413 SCV000579537 uncertain significance Hypertrophic cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score unknown significance
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000475413 SCV000564443 uncertain significance Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.3169G>A (p.Gly1057Ser) variant in MYH7 has been reported in 9 individuals with hypertrophic cardiomyopathy (PS4_Moderate; PMID:15358028; PMID:24510615; Partners LMM ClinVar SCV000059494.5; SHaRe consortium, PMID: 30297972). This variant was identified in 1/66738 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; PS4_Moderate; PP3
GeneDx RCV000766440 SCV000208528 uncertain significance not provided 2018-12-03 criteria provided, single submitter clinical testing The G1057S variant of uncertain significance in the MYH7 gene has been reported in individuals with hypertrophic cardiomyopathy (HCM) and/or referred for HCM genetic testing (Van Driest et al., 2004; Ingles et al., 2005; Kapplinger et al., 2014; Walsh et al., 2017), though robust clinical and segregation information was not provided for most cases. Nevertheless, the G1057S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The G1057S 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-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000475413 SCV000546183 likely pathogenic Hypertrophic cardiomyopathy 2017-04-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1057 of the MYH7 protein (p.Gly1057Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs397516179, ExAC 0.001%) . This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 15358028, 27532257, Invitae) and in four individuals diagnosed with HCM or referred for HCM genetic testing (PMID: 24510615). ClinVar contains an entry for this variant (Variation ID: 42950). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, this variant is a rare missense change that is predicted to be deleterious and has been observed in multiple unrelated individuals with hypertrophic cardiomyopathy. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035843 SCV000059494 uncertain significance not specified 2017-08-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu1057Se r variant in MYH7 has been reported in 9 individuals with HCM (Van Driest 2004, Kapplinger 2014, LMM data), but was also present in one of these individual's un affected, elderly parent. This variant has also been identified in 1/66738 Europ ean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs397516179). Glycine (Gly) at position 1057 is highly conserve d in mammals and across evolutionarily distant species and the change to serine (Ser) was predicted to be pathogenic using a computational tool clinically valid ated by our laboratory. This tool's pathogenic prediction is estimated to be cor rect 94% of the time (Jordan 2011). In summary, while there is some suspicion fo r a pathogenic role, the clinical significance of the p.Glu1057Ser variant is un certain.

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