ClinVar Miner

Submissions for variant NM_000258.2(MYL3):c.461G>A (p.Arg154His) (rs104893749)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201878 SCV000256645 likely pathogenic Familial hypertrophic cardiomyopathy 1 2015-03-11 criteria provided, single submitter research The MYL3 Arg154His variant has previously been reported in a young individual with massive hypertrophy, resulting in mid cavity obstruction, and was absent in >350 controls(Poetter K, et al., 1996). This variant is absent in the 1000 genomes project (http://www.1000genomes.org/) and present at a low frequency in the Exome Aggregation Consortium dataset (MAF=0.00002471; http://exac.broadinstitute.org/). We identified this variant in 1 HCM proband (IVS=32mm) with no family history of disease or SCD. Interestingly, other rare variants resulting in different amino acid substitutions at this position (Arg154Leu, Arg154Cys) have also been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect, but no prediction is called by PolyPhen-HCM. Furthermore, an in vitro study has shown mutations in MYL3 to affect myosin binding (Lossie J, et al., 2012) but it is uncertain how this translates in the biological setting. Given that this MYL3 Arg154His is extremely rare in the general population, and that it has been identified independently in 2 other unrelated HCM cases (Poetter K, et al., 1996; LMM ClinVar: SCV000035363), we have classified MYL3 Arg154His as "likely pathogenic". Further supporting evidence is needed to fully establish its role in the disease pathogenesis of HCM.
Ambry Genetics RCV000253839 SCV000318462 uncertain significance Cardiovascular phenotype 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia RCV000491772 SCV000298146 uncertain significance Familial restrictive cardiomyopathy 1 2016-05-01 no assertion criteria provided clinical testing
GeneDx RCV000766487 SCV000250969 uncertain significance not provided 2018-09-10 criteria provided, single submitter clinical testing The R154H variant of uncertain significance in the MYL3 gene has been reported multiple times in association with HCM (Poetter et al., 1996; Miller et al., 2013; Burns et al., 2017; Ross et al., 2017; Walsh et al., 2017), although no segregation data were provided. This variant has also been observed in multiple unrelated individuals referred for cardiomyopathy genetic testing at GeneDx; however, several individuals harbored additional cardiogenetic variants, including pathogenic variants in other genes. In addition, no informative segregation data are available to further clarify the role of this variant in disease. The R154H variant has also been observed in two individuals without HCM from the offspring cohort in the Framingham Heart Study (Bick et al., 2012), and is observed in 8/277,124 (0.003%) alleles from individuals of various ethnic backgrounds in large population cohorts (Lek et al., 2016).Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Pathogenic/likely pathogenic missense variants in nearby residues (M149V, M149T, A151T, E152K) have been reported at GeneDx and/or in HGMD in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein. Furthermore, in vitro functional studies suggest that R154H causes reduced binding affinity for the cardiac myosin heavy chain (Lossie et al., 2012); however, it is unclear what impact this variant may have on protein function in vivo. Although a different missense variant at the same residue (R154C) has also been reported in association with HCM (Lopes et al., 2013; Zou et al., 2013), the clinical significance of this variant remains to be definitively determined. Finally, R154H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000552674 SCV000623772 uncertain significance Hypertrophic cardiomyopathy 2017-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 154 of the MYL3 protein (p.Arg154His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs104893749, ExAC 0.01%). This variant has been reported in the literature in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 8673105, 27532257, 28790153). ClinVar contains an entry for this variant (Variation ID: 14062). An experimental study has shown that this variant causes a lower affinity of the myosin heavy chain (PMID: 22131351). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036025 SCV000059677 uncertain significance not specified 2018-12-14 criteria provided, single submitter clinical testing The p.Arg154His variant in MYL3 has been identified in at least 7 individuals wi th HCM (Poetter 1996, Ross 2017, Walsh 2016, Wojciak pers. comm., Ambry pers. co mm, LMM data). The variant segregated with disease in one affected family member (Ross 2017). This variant has also been identified in 8/277124 chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104893749). In vitro functional studies provide some evidence that the p.Arg15 4His variant may impact protein function (Lossie 2012); however, these types of assays may not accurately represent biological function. Computational predictio n tools and conservation analysis suggest that the p.Arg154His variant may impac t the protein, though this information is not predictive enough to determine pat hogenicity. In summary, the clinical significance of the p.Arg154His variant is uncertain. ACMG/AMP criteria applied: PP3, PS3_Supporting.
Leiden Muscular Dystrophy (MYL3) RCV000015106 SCV000045770 not provided Familial hypertrophic cardiomyopathy 8 2012-03-18 no assertion provided curation
OMIM RCV000015106 SCV000035363 pathogenic Familial hypertrophic cardiomyopathy 8 1996-05-01 no assertion criteria provided literature only

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