ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.611G>T (p.Arg204Leu) (rs397516260)

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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 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 RCV000154508 SCV000208685 uncertain significance not specified 2015-08-05 criteria provided, single submitter clinical testing Although the R204L variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge, this variant has been reported as variant of unknown significance in several individuals referred for clinical testing at other laboratories (Landrum et al., 2014). The R204L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R204L 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. This substitution occurs at a position that is conserved in mammalian species. Missense mutations in nearby residues (A200T; I201T) have been reported in the Human Gene Mutation Database in association with hypertrophic cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724202 SCV000231502 uncertain significance not provided 2015-12-03 criteria provided, single submitter clinical testing
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 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 204 of the MYH7 protein (p.Arg204Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected 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). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. A different missense substitution at this codon (p.Arg204His) has been determined to be pathogenic (PMID: 12707239, 27247418, 24111713, 27841901, 23816408, 24865491, 27532257). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. 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

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