ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5134C>T (p.Arg1712Trp) (rs121913650)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480992 SCV000565293 likely pathogenic not provided 2017-07-26 criteria provided, single submitter clinical testing The R1712W likely pathogenic variant has been reported previously in association with HCM (Hougs L et al., 2005; Jensen M et al., 2012; Hagan C et al., 2013). Hougs et al. (2005) initially reported R1712W in two Danish individuals with HCM; R1712W co-segregated with disease in one family, however the other proband also harbored a variant in the MYL2 gene. In a subsequent study, Jensen et al. (2012) reported that a relative of a proband with HCM, both of whom carry R1712W, did not meet clinical criteria of HCM in follow up at the age of 26-years-old. Another study identified R1712W in a family with HCM, however this family also harbored a variant in the MT-CYB mitochondrial gene (Hagan et al., 2013). Three of six R1712W carriers who also harbored the homoplasmic MT-CYB variant had HCM, and the one individual who harbored only R1712W in the MYH7 gene was asymptomatic for HCM at the age of 14-years-old (Hagan et al., 2013). A variant at this same residue (R1712Q) has been reported in association with HCM, but has also been shown not to co-segregate with disease (Pan S et al., 2012; Mook et al. 2013).Nevertheless, the R1712W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the R1712W 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, and this substitution occurs at a position that is conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae RCV000546277 SCV000623734 pathogenic Hypertrophic cardiomyopathy 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1712 of the MYH7 protein (p.Arg1712Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 15483641, Invitae) with evidence of co-segregation with disease in one family (PMID: 15483641). ClinVar contains an entry for this variant (Variation ID: 14118). 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). A different missense substitution at this codon (p.Arg1712Gln) has been determined to be likely pathogenic (PMID: 18403758, 21511876, 23785128, 24510615, 27247418, 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000605244 SCV000710842 uncertain significance not specified 2019-02-25 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
OMIM RCV000015175 SCV000035432 pathogenic Familial hypertrophic cardiomyopathy 1 2005-02-01 no assertion criteria provided literature only

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