ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3578G>A (p.Arg1193His) (rs397516187)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000035858 SCV000564445 uncertain significance Primary dilated cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.3578G>A (p.Arg1193His) variant in MYH7 has been reported in 5 individuals with dilated cardiomyopathy (Partners LMM ClinVar SCV000059509.5) but has also been identified in 1/51248 European chromosomes by ExAC and this position is indicated as a possible low-quality site due to coverage ((http://exac.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if variant is absent or rare in large population studies, PS4 criterion was not applied (PMID:29300372). 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 dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3
GeneDx RCV000158611 SCV000208546 uncertain significance not provided 2019-03-22 criteria provided, single submitter clinical testing The R1193H variant in the MYH7 gene has been published in one patient with DCM (Lakdawala N etal., 2012). Although R1193H results in a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, the R1193 residue is conserved across species. Another missense variant affecting the same residue (R1193S) has also been reported in association with DCM (Villard E et al., 2005). Furthermore, R1193H was not observed in approximately 6,400 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 summary, R1193H in the MYH7 gene is interpreted as a variant of unknown significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035858 SCV000059509 likely pathogenic Primary dilated cardiomyopathy 2016-07-22 criteria provided, single submitter clinical testing The p.Arg1193His variant in MYH7 has been identified by our laboratory in 6 Caucasian individuals with DCM and segregated with disease in 4 affected relatives from 3 families, including one obligate carrier (Lakdawala 2012, LMM data). This variant has also been identified in 1/51248 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516187). Arginine (Arg) at position 1193 is highly conserved in mammals and across evolutionarily distant species and the change to histidine (His) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In addition, a different likely pathogenic variant (p.Arg1193Ser) at this position has been reported in 4 family members with DCM (Villard 2005), supporting that a change at this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg1193His variant is likely pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627139 SCV000747955 likely pathogenic Familial dilated cardiomyopathy 2017-07-24 criteria provided, single submitter clinical testing

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