ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.470C>T (p.Ala157Val) (rs397516353)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000465603 SCV000059951 pathogenic Hypertrophic cardiomyopathy 2020-10-05 criteria provided, single submitter clinical testing The p.Ala157Val variant in TNNI3 has been reported in > 20 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 7 affected individuals from at least 6 families (Richard 2003 PMID: 12707239; Mogensen 2004 PMID: 15607392; Brito 2005 PMID: 16335287, Curila 2009 PMID: 19645627; van den Wijngaard 2011 PMID: 21533915; Coppini 2014 PMID: 25524337; Walsh 2017 PMID: 27532257; LMM internal data). This variant has also been reported in 2 individuals with sudden death at a young age (van den Wijngaard 2011 PMID: 21533915) and in one individual with DCM (Walsh 2017 PMID: 27532257). Additionally, the p.Ala157Val variant has been reported by other clinical laboratories in ClinVar (Variation ID: 43388) and was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting.
GeneDx RCV000159227 SCV000209173 pathogenic not provided 2018-10-10 criteria provided, single submitter clinical testing The A157V variant in the TNNI3 gene has been published previously in association with HCM (Richard et al., 2003; Mogensen et al., 2004; Brito et al., 2005; Curila et al., 2009; van den Wijngaard et al., 2011; Zou et al., 2013; Rowin et al., 2014; Coppini et al., 2014; Berge et al., 2014; Captur et al., 2014; Lopes et al., 2015; Walsh et al., 2017). This variant has been shown to segregate with disease in several unrelated families referred for genetic testing at GeneDx and in published literature (Mogensen et al., 2004; Curila et al., 2009). Furthermore, the A157V variant has been identified in other unrelated individuals referred for genetic testing of HCM at GeneDx. Considering all publications and internal data, it is possible that this variant exhibits reduced penetrance and/or is associated with milder/later-onset disease. Although the A157V variant results in a conservative amino acid substitution, it occurs at a position that is conserved through mammals. Finally, the A157V variant is not observed in large population cohorts (Lek et al., 2016). In summary, A157V in the TNNI3 gene is interpreted as a pathogenic variant.
Invitae RCV000465603 SCV000551893 pathogenic Hypertrophic cardiomyopathy 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 157 of the TNNI3 protein (p.Ala157Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 12707239, 16335287, 24111713, 25524337, 25239116, 23283745, 24704860, 27532257), been shown to segregate with HCM in several families (PMID: 26506446, 21533915, 15607392, 19645627). It has also been reported in an individual with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43388). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare missense variant that has been reported in individuals and families with HCM. This variant is also predicted to affect protein function and mRNA splicing. For these reasons it has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170616 SCV001333205 pathogenic Cardiomyopathy 2019-04-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174966 SCV001338448 pathogenic Primary familial hypertrophic cardiomyopathy 2020-04-06 criteria provided, single submitter clinical testing Variant summary: TNNI3 c.470C>T (p.Ala157Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249082 control chromosomes (gnomAD). c.470C>T has been reported in the literature in several individuals affected with Hypertrophic Cardiomyopathy (Richard_2003, Brito_2005, Mogensen_2004, Curila_2009, Zheng_2016, Walsh_2017), and in many families the variant was demonstrated to segregate with the disease, (Richard_2003, Mogensen_2004, Curila_2009, Zheng_2016). The phenotypic manifestations ranged from clinically silent to sudden cardiac death, in addition the variant was also reported in an individual with dilated cardiomyopathy (Walsh_2017); these reports might indicate a variable penetrance. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in a decreased level of the TNNI3 protein in a mammalian cell based expression system (Zheng_2016). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, Klinikum rechts der Isar RCV000578464 SCV000680411 pathogenic Familial hypertrophic cardiomyopathy 7 2017-11-08 no assertion criteria provided clinical testing

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