ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.268C>T (p.Pro90Ser) (rs397516451)

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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 RCV000036565 SCV000060220 uncertain significance not specified 2010-11-30 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Pro80Ser va riant has not been reported in the literature. Proline (Pro) at position 80 is highly conserved across several evolutionarily distant species. In addition, th is variant was predicted to be pathogenic using a novel computational tool (a cu stomized sarcomere-specific PolyPhen tool, which was validated using a set of ca rdiomyopathy variants with well-established clinical significance). This tool's pathogenic prediction is estimated to be correct 94% of the time, which suggests but does not prove that this variant is pathogenic. However, in the absence of additional supporting data, the clinical significance of this variant cannot be determined at this time.
Invitae RCV000204383 SCV000260850 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2015-09-26 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 80 of the TNNT2 protein (p.Pro80Ser). The serine residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant was reported in one family affected with hypertrophic cardiomyopathy (HCM) (PMID: 22112859). ClinVar contains an entry for this variant (Variation ID: 43620). A computational algorithm designed to assess the pathogenicity of missense variants in TNNT2 with regard to hypertrophic cardiomyopathy predicted this sequence change to be pathogenic. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, this is a rare missense change that has been reported in one affected family and is predicted to have an impact on protein function. However there is no functional or segregation data at this time to confirm that this variant is deleterious. For these reasons, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000617520 SCV000740221 uncertain significance Cardiovascular phenotype 2017-09-22 criteria provided, single submitter clinical testing The p.P80S variant (also known as c.238C>T), located in coding exon 7 of the TNNT2 gene, results from a C to T substitution at nucleotide position 238. The proline at codon 80 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a proband and his mother, both with hypertrophic cardiomyopathy (HCM), though the proband carried TNNT2 p.F110I in trans (Otsuka H et al. Circ. J. 2012;76:453-61). This variant was also detected in an HCM cohort; however, clinical details were limited (Walsh R et al. Genet. Med. 2017;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Blueprint Genetics RCV000788418 SCV000927518 likely pathogenic not provided 2018-01-23 criteria provided, single submitter clinical testing

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