ClinVar Miner

Submissions for variant NM_000258.2(MYL3):c.281G>A (p.Arg94His) (rs199474703)

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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 RCV000824445 SCV000059672 likely pathogenic Hypertrophic cardiomyopathy 2017-12-15 criteria provided, single submitter clinical testing The p.Arg94His variant in MYL3 has been identified in 8 individuals with HCM and segregated with disease in 10 affected relatives across these families (Fokstue n 2008, Zou 2013, Nomura 2016, LMM data). This variant has also been identified in 1/111666 of European chromosomes and 1/33582 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1994747 03). Computational tools suggest that this variant does not impact the protein b ut these data are not predictive enough to rule out pathogenicity and do not out weigh the above evidence supporting pathogenicity. In summary, although addition al studies are required to fully establish its clinical significance, the p.Arg9 4His variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_Strong; PM2; P S4_Moderate; BP4.
GeneDx RCV000024468 SCV000208878 pathogenic not provided 2012-01-23 criteria provided, single submitter clinical testing The Arg94His mutation has been reported in one individual diagnosed with HCM, and this mutation was absent from 192 control alleles (Fokstuen et al. 2008). Another mutation affecting the same residue, Arg94Cys, has been observed in two unrelated individuals tested for HCM at GeneDx. Arg94His occurs at a position that is conserved across other species (Fokstuen et al. 2008). The NHLBI ESP Exome Variant Server reports Arg94His was not observed in approximately 3,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Therefore, the presence of this mutation indicates an increased risk of developing HCM. The variant is found in HCM panel(s).
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769168 SCV000900543 likely pathogenic Cardiomyopathy 2017-01-23 criteria provided, single submitter clinical testing
Invitae RCV000824445 SCV000965343 pathogenic Hypertrophic cardiomyopathy 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 94 of the MYL3 protein (p.Arg94His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hypertrophic cardiomyopathy in families suggested to have a common ancestor (PMID: 26443374), and it has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 18409188, 23283745, 27532257). ClinVar contains an entry for this variant (Variation ID: 31777). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Leiden Muscular Dystrophy (MYL3) RCV000024468 SCV000045771 not provided not provided 2012-03-18 no assertion provided curation
Department of Cardiovascular and Internal Medicine,Kanazawa University Graduate School of Medicine RCV000491596 SCV000579494 pathogenic Familial hypertrophic cardiomyopathy 8 2015-08-01 no assertion criteria provided research

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