Submissions for variant NM_001276345.2(TNNT2):c.268C>A (p.Pro90Thr)

dbSNP: rs397516451

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159273	SCV000209219	uncertain significance	not provided	2018-02-20	criteria provided, single submitter	clinical testing	The P80T variant of uncertain significance in the TNNT2 gene has not been published as pathogenic or benign to our knowledge. P80T is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species, and in silico analysis predicts P80T is probably damaging to the protein structure/function. Furthermore, P80T is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant has also been identified in individuals referred for HCM genetic testing at GeneDx; however, segregation studies have been uninformative thus far. Moreover, while a variant in the same residue (P80S) has been reported to segregate with disease in a family with HCM and LVNC, the proband was also found to harbor a second variant in TNNT2 that likely contributed to his phenotype (Otsuka H et al., 2012). Thus, P80T lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798538	SCV002042841	uncertain significance	Cardiomyopathy	2021-01-12	criteria provided, single submitter	clinical testing
Invitae	RCV001850238	SCV002179971	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2021-10-11	criteria provided, single submitter	clinical testing	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. 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 C0"). ClinVar contains an entry for this variant (Variation ID: 181611). This missense change has been observed in individual(s) with clinical features of TNNT2-related conditions (PMID: 31737537). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with threonine at codon 80 of the TNNT2 protein (p.Pro80Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine.
Genome-Nilou Lab	RCV003453216	SCV004181532	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453217	SCV004181533	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453215	SCV004181534	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing