ClinVar Miner

Submissions for variant NM_000432.3(MYL2):c.488A>C (p.Glu163Ala) (rs397516407)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000639678 SCV000761258 likely pathogenic Familial hypertrophic cardiomyopathy 10 2017-11-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 163 of the MYL2 protein (p.Glu163Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant was reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24793961). ClinVar contains an entry for this variant (Variation ID: 43480). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036409 SCV000060064 likely pathogenic Hypertrophic cardiomyopathy 2013-02-11 criteria provided, single submitter clinical testing The Glu163Ala variant in MYL2 has not been reported in the literature, but has b een identified by our laboratory in 2 individuals with HCM (LMM unpublished data ). This variant has not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs., which increases the likelihood that the variant is patho genic. However, we cannot exclude that it may be common in other populations. Gl utamic acid (Glu) at position 163 is highly conserved in mammals and across evol utionarily distant species and the change to alanine (Ala) was predicted to be p athogenic using a computational tool clinically validated by our laboratory. Thi s tool's pathogenic prediction is estimated to be correct 94% of the time (Jorda n 2011). In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance.

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