ClinVar Miner

Submissions for variant NM_000432.3(MYL2):c.484G>A (p.Gly162Arg) (rs199474814)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000627045 SCV000747750 uncertain significance Cardiomyopathy 2018-01-09 criteria provided, single submitter clinical testing This heterozygous variant in the MYL2 gene was identified in a young patient diagnosed with restrictive cardiomyopathy.
GeneDx RCV000119380 SCV000208869 pathogenic not provided 2015-09-14 criteria provided, single submitter clinical testing This mutation is denoted p.Gly162Arg (G162R) at the protein level and c.484 G>A at the cDNA level. The Gly162Arg mutation in the MYL2 gene has been reported previously in association with HCM (Olivotto I et al., 2008). Olivotto (2008) identified this mutation in one individual with HCM and it was found to be absent from 300 control chromosomes (Olivotto I et al., 2008). Gly162Arg results in a non-conservative amino acid substitution of a non-polar Glycine residue with a polar Arginine residue. Another mutation affecting the same codon, Gly162Glu, has been seen in other unrelated individuals at GendDX. In addition, another nearby missense mutation, Asp166Val, has been associated with HCM, further supporting the functional importance of this region of the protein (Cirino AL et al., GeneReviews). The Gly162Arg mutation was not observed in up to 400 control alleles from individuals of Caucasian and African American ancestry tested at GeneDx, indicating it is not a common benign variant in these populations. The variant is found in HCM panel(s).
Invitae RCV000226326 SCV000284835 uncertain significance Familial hypertrophic cardiomyopathy 10 2016-02-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 162 of the MYL2 protein (p.Gly162Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (rs199474814, ExAC no frequency). This variant has been reported in an individual affected with hypertrophic cardiomyopathy, however there currently is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 18533079). ClinVar contains an entry for this variant (Variation ID: 132976). A computational algorithm designed to assess the pathogenicity of variants in MYL2 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). Furthermore, in an experimental study this variant was shown to affect cardiac muscle fibre function in-vitro (PMID: 23343568). However, the clinical significance of this finding is unclear. In summary, this variant is a rare missense change with uncertain impact on protein function. Information regarding segregation with disease and functional effect is currently insufficient. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156897 SCV000206618 likely pathogenic Hypertrophic cardiomyopathy 2018-02-07 criteria provided, single submitter clinical testing The p.Gly162Arg variant in MYL2 has been reported as a de novo occurrence in two individuals with HCM, one of whom was also reported to have AV and RBB block (O livotto 2008, personal communication, LMM data) and in a third individual with L VH, reduced EF and ST segment abnormality (LMM data). This variant was absent fr om large population studies, but has been reported in ClinVar (Variation ID: 132 976). In vitro functional studies provide some evidence that the p.Gly162Arg var iant may impact protein function (Burghardt 2013); however, these types of assay s sometimes do not accurately represent biological function. Glycine (Gly) at po sition 162 is highly conserved in evolution and the change to arginine (Arg) was predicted to be pathogenic using a computational tool clinically validated by o ur laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly162Arg variant is likely pathogenic. ACMG/AMP Criteria applied: PM6_Strong; PM2; PS3_Supporting; PP3; PS4 _Supporting.
Leiden Muscular Dystrophy (MYL2) RCV000119380 SCV000154287 not provided not provided no assertion provided not provided
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000119380 SCV000280386 likely pathogenic not provided 2015-03-12 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gly162Arg (p.G162R; c.484G>A) in exon 7 of the MYL2 gene (NM_000432.3) Mutations in the myosin ventricular regulatory light chain 2 (MYL2 gene) have been reported in a small percentage of patients with HCM (estimated range 1-5%). The variant has been reported in one other case of HCM, and it was de novo in that patient. Olivotto et al., 2008 (last author Cecchi) reported the “E162R” variant in one individual with HCM; however, we contacted the authors and learned that this is a typo that actually indicates G162R (as indicated by LMM, ClinVar, HGMD, etc.). Additional details regarding this patient’s phenotype were not given in the paper. The authors report to us by email that the variant was de novo in the young girl with HCM, and that her parents were studied and found to be clinically unaffected, supporting pathogenicity (Francesca Girolami, personal communication). Harvard’s LMM has reported a different variant at the same amino acid in 3 probands with HCM: p.Gly162Glu in the MYL2 gene (Alfares et al. 2015). They classify this p.Gly162Glu variant as “likely pathogenic”. One piece of evidence unique to their lab is that the change to glutamic acid (Glu) was predicted to be pathogenic using a computational tool, validated by the LMM laboratory, which uses a set of cardiomyopathy variants with well-established clinical significance. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Our patient’s variant at this same position (Gly162Arg) is also predicted to be pathogenic by the same tool (LMM unpublished data). The Gly162Arg variant results in a non-conservative amino acid substitution of a nonpolar Glycine with a positively charged Arginine, which has a much bulkier side chain. It is located in exon 7 out of 7 exons. In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. The Glycine at codon 162 is entirely conserved across vertebrate species. Neighboring amino acids are also entirely conserved. One other variant listed in HGMD has been associated with disease at a nearby codon (+/- 10): Asp166Val (as of January 2014). In vitro studies of this variant indicate that it results in altered protein function, although these studies do not always mirror effects in vivo (Berghardt et al. 2013). The variant is very rare: In total it has not been seen in ~60,000 laboratory controls, published controls, and individuals from publicly available population datasets. There is no variation at codon 162 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 2/17/2015). Our patient is Caucasian. It is absent from 1000 Genomes. It is also absent from the ExAC database, which includes 60,000 exomes from disease-specific and population genetic studies (with efforts made to exclude individuals with severe pediatric diseases). The variant was not observed in the following laboratory and published control samples: absent 150 Caucasian individuals of Italian origin (Olivotto et al. 2008).

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