Submissions for variant NM_001276345.2(TNNT2):c.254T>G (p.Val85Gly)

gnomAD frequency: 0.00001  dbSNP: rs730881095

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159270	SCV000209216	uncertain significance	not provided	2023-10-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22958901, 34935411)
Invitae	RCV000460783	SCV000541913	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 75 of the TNNT2 protein (p.Val75Gly). This variant is present in population databases (rs730881095, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 181609). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function with a positive predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193336	SCV001362090	uncertain significance	not specified	2019-12-16	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.224T>G (p.Val75Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251036 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.224T>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002426782	SCV002729356	uncertain significance	Cardiovascular phenotype	2023-06-12	criteria provided, single submitter	clinical testing	The p.V75G variant (also known as c.224T>G), located in coding exon 7 of the TNNT2 gene, results from a T to G substitution at nucleotide position 224. The valine at codon 75 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in a population-based longitudinal study in an individual without overt cardiomyopathy, and in an individual from a pediatric dilated cardiomyopathy cohort (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9; Khan RS et al. J Am Heart Assoc. 2022 Jan;11(1):e022854). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV003453213	SCV004177943	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453214	SCV004177944	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453212	SCV004177945	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998388	SCV004834199	uncertain significance	Cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 75 of the TNNT2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 34935411). This variant has been identified in 2/251036 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.