ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.526G>A (p.Val176Met) (rs727503501)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000152074 SCV000200712 uncertain significance not specified 2014-01-22 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Val176Met v ariant in TNNI3 has been reported in 2 individuals with HCM (Lopes 2013) and has been now been identified by our laboratory in 2 individuals with HCM. It has no t been identified in large population studies. Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, and PolyPhen2) suggest that t his variant may impact the protein, though this information is not predictive en ough to determine pathogenicity. Although this data supports that the Val176Met variant may be pathogenic, additional studies are needed to fully assess its cli nical significance.
Blueprint Genetics RCV000788773 SCV000928011 likely pathogenic not provided 2018-10-19 criteria provided, single submitter clinical testing
Invitae RCV001036762 SCV001200142 uncertain significance Hypertrophic cardiomyopathy 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 176 of the TNNI3 protein (p.Val176Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25524337, 27532257, 30384889, 23396983, Invitae). ClinVar contains an entry for this variant (Variation ID: 165513). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5
Blueprint Genetics RCV000157532 SCV000207278 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-05-05 no assertion criteria provided clinical testing

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