ClinVar Miner

Submissions for variant NM_001001430.2(TNNT2):c.311C>T (p.Ala104Val) (rs727504245)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476946 SCV000541918 likely pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 104 of the TNNT2 protein (p.Ala104Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs727504245, ExAC 0.01%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 9140840, 27532257, 28408708). This variant has been also been observed in two additional individuals with hypertrophic cardiomyopathy (PMID: 23396983). However, in those individuals pathogenic alleles were also identified in different genes, which suggests that this c.311C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 177633). A computational algorithm designed to assess the pathogenicity of variants in TNNT2 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000154215 SCV000203868 uncertain significance not specified 2017-08-15 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala104Val variant in TNNT2 has been identified in 4 individuals with HCM (Nakajima-Taniguchi 1997, Pasquale 2012, LMM data). It has also been identified in 1/8654 East Asian chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs727504245). In vitro functional studies provide some evidence that the p.Ala104Val variant may impact protein function (Palm 2001, Harada 2004). However, these types of assays may not accurately represent biological function. This variant was also 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, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala104Val variant is uncertain.

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