ClinVar Genomic variation as it relates to human health

This heterozygous variant in the MYL2 gene was identified in a young patient diagnosed with restrictive cardiomyopathy.

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 (Olivotto 2008, personal communication, LMM data) and in a third individual with LVH, reduced EF and ST segment abnormality (LMM data). This variant was absent from large population studies, but has been reported in ClinVar (Variation ID: 132976). In vitro functional studies provide some evidence that the p.Gly162Arg variant may impact protein function (Burghardt 2013); however, these types of assays sometimes do not accurately represent biological function. Glycine (Gly) at position 162 is highly conserved in evolution and the change to arginine (Arg) 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 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.

Published in vitro and in vivo functional studies demonstrate a damaging effect on protein function (Manivannan et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#132976; ClinVar); This variant is associated with the following publications: (PMID: 23343568, 18533079, 28991257, 32368696, 36291626, 32453731)

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 162 of the MYL2 protein (p.Gly162Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or congenital heart disease (PMID: 18533079, 27532257, 28991257; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 132976). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYL2 function (PMID: 23343568, 32453731). For these reasons, this variant has been classified as Pathogenic.

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).