ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.611G>T (p.Arg204Leu)

dbSNP: rs397516260
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154508 SCV000204179 uncertain significance not specified 2014-04-17 criteria provided, single submitter clinical testing The Arg204Leu variant in MYH7 has not been reported in the literature, but has b een identified by our laboratory in 4 Caucasian individuals with HCM, one of who m also carried another variant of unknown significance in MYBPC3. This variant h as not been identified in large European American and African American populatio ns by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS); oth er populations have not been examined adequately. Arginine (Arg) at this positio n is conserved in mammals and chickens, but this part of the MYH7 protein appear s to be less well conserved in more distantly related species. In addition, this variant was predicted to be benign using a computational tool clinically valida ted by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). While the presence in multiple affected individua ls and absence from the general population are consistent with a role in disease , the computational data suggest that the variant may not impact the normal func tion of the protein. In summary, additional information is needed to fully asses s the clinical significance of the Arg204Leu variant.
GeneDx RCV000724202 SCV000208685 likely pathogenic not provided 2023-05-10 criteria provided, single submitter clinical testing Reported in association with cardiomyopathy and unexplained cardiac arrest (Walsh et al., 2017; Hathaway et al., 2021; Grondin et al., 2022); however, details regarding clinical presentation, segregation data, and other co-occurring variants were not provided; Reported in a patient with erythropoietic porphyria who underwent exome sequencing (Wang et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24111713, 27247418, 27841901, 21310275, 12707239, 33673806, 27532257, 35352813, 29300372, 26338694)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000416304 SCV000485049 likely pathogenic Cardiomyopathy 2016-05-18 criteria provided, single submitter clinical testing
Invitae RCV000628899 SCV000749807 pathogenic Hypertrophic cardiomyopathy 2023-12-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 204 of the MYH7 protein (p.Arg204Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 177869). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be tolerated (PMID: 21310275). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000724202 SCV000928265 likely pathogenic not provided 2019-03-06 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000416304 SCV003838520 likely pathogenic Cardiomyopathy 2023-01-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV003362694 SCV004084724 likely pathogenic Cardiovascular phenotype 2023-07-17 criteria provided, single submitter clinical testing The p.R204L variant (also known as c.611G>T), located in coding exon 5 of the MYH7 gene, results from a G to T substitution at nucleotide position 611. The arginine at codon 204 is replaced by leucine, an amino acid with dissimilar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been detected in four individuals from a hypertrophic cardiomyopathy (HCM) genetic testing cohort; however, clinical details were limited (Walsh R et al. Genet Med, 2017 02;19:192-203). Another alteration at the same codon, p.R204H (c.611G>A), has also been reported in association with HCM (Richard P et al. Circulation. 2003). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Eurofins Ntd Llc (ga) RCV000724202 SCV000231502 uncertain significance not provided 2015-12-03 flagged submission clinical testing

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