ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4258C>T (p.Arg1420Trp) (rs145213771)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148697 SCV000190426 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000758078 SCV000564450 likely pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.4258C>T (p.Arg1420Trp) variant in MYH7 has been reported in >10 individuals with hypertrophic cardiomyopathy (PS4_Moderate; PMID:27532257; PMID:20624503; PMID:23140321; PMID:15358028; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000059548.5). This variant has been identified in 1/66734 European chromosomes (PM2; http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Based on criteria selected, this variant would be classified as uncertain significance; however the expert panel felt that the available evidence was sufficiently borderline and the presence of additional probands not counted due to potential cohort overlap in publications warranted an adjustment in classification. Therefore, the final classification was likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM2; PS4_Moderate; PP3
GeneDx RCV000035897 SCV000208581 uncertain significance not specified 2016-01-18 criteria provided, single submitter clinical testing The R1420W variant was first reported by Van Driest et al. (2004) in one individual with HCM and was absent from 400 control chromosomes. In addition, R1420W has been reported in five Norwegian probands with HCM as well as two unrelated French patients with HCM, however no familial segregation data were reported for these individuals (Berge et al., 2014; Millat et al., 2010). Zou et al. (2013) reported R1420W in one Chinese patient with HCM, though this individual also harbored a second MYH7 variant. The R1420W variant has been seen in one other individual referred for HCM testing at GeneDx, though family studies are not available to discern whether this variant co-segregates with disease. Additionally, R1420W is reported in ClinVar as a variant of uncertain significance by a different clinical laboratory (ClinVar SCV000059548.3; Landrum et al., 2016). The R1420W variant was not observed with any significant frequency 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. Moreover, R1420W 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. Furthermore, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035897 SCV000059548 uncertain significance not specified 2015-12-02 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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