ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.566C>T (p.Ser189Phe) (rs727504246)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154216 SCV000203870 likely pathogenic Hypertrophic cardiomyopathy 2010-07-26 criteria provided, single submitter clinical testing The Ser179Phe variant in TNNT2 has been reported in one consanguineous family wi th HCM where it was present in 2 heterozygous individuals with mild HCM and in 1 homozygous individual who died early due to a severe form of HCM (Ho 2000). Thi s variant has also been identified by our laboratory in 1 adult and 1 child with HCM, and was absent from large population studies. The Ser179Phe variant was pr edicted 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), which strongly supports but does not prove that the Ser1 79Phe variant is pathogenic. In summary, this variant is likely to be pathogenic and causative for HCM, though evidence suggests a milder form when present in t he heterozygous state.
Invitae RCV000471745 SCV000541923 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 179 of the TNNT2 protein (p.Ser179Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family with clinical findings consistent with hypertrophic cardiomyopathy (HCM) , including a homozygous individual with severe HCM (PMID: 27532257, 11034944). Additionally, it has been reported in two individuals affected with HCM tested at a diagnostic laboratory (PMID: 24033266). ClinVar contains an entry for this variant (Variation ID: 177634). 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). In summary, this is a rare variant that is absent from the general population, but has been reported in individuals and a family affected with HCM  and is expected to cause a deleterious effect on TNNT2 protein function. For these reasons this variant has been classified as Pathogenic.
Ambry Genetics RCV000617860 SCV000736253 likely pathogenic Cardiovascular phenotype 2018-01-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation

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