Submissions for variant NM_001276345.2(TNNT2):c.601-7G>A

gnomAD frequency: 0.00004  dbSNP: rs369759523

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036604	SCV000060259	uncertain significance	not specified	2018-04-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Color Diagnostics, LLC DBA Color Health	RCV001175857	SCV001339636	uncertain significance	Cardiomyopathy	2023-03-15	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -7 position of intron 11 of the TNNT2 gene. Splice prediction tools suggest that this variant may impact RNA splicing by creating a new splice acceptor site. An RNA study using a minigene system was inconclusive regarding the variant impact on splicing (PMID: 25849606). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (https://www.cardiodb.org/). This variant has also been identified in 23/248878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for TNNT2-related disorder, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001247591	SCV001421021	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 of the TNNT2 gene. It does not directly change the encoded amino acid sequence of the TNNT2 protein. This variant is present in population databases (rs369759523, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25849606). ClinVar contains an entry for this variant (Variation ID: 43656). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNNT2 function (PMID: 25849606). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
GeneDx	RCV001689586	SCV001907453	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001175857	SCV004816720	uncertain significance	Cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -7 position of intron 11 of the TNNT2 gene. Splice prediction tools suggest that this variant may impact RNA splicing by creating a new splice acceptor site. An RNA study using a minigene system was inconclusive regarding the variant impact on splicing (PMID: 25849606). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (https://www.cardiodb.org/). This variant has also been identified in 23/248878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for TNNT2-related disorder, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001254738	SCV001430823	uncertain significance	Hypertrophic cardiomyopathy	2019-11-26	no assertion criteria provided	research	TNNT2 c.571-7G>A has been reported in 1 HCM proband (LMM, www.cardiodb.org/acgv/acgv_variant.php?id=49287) and 1 cardiomyopathy case but analysis of the functional splicing impact was inconclusive (Millat G, et al., 2015). The variant is also present at the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.00009605 which is higher then expected for HCM and suggests that the occurrence of the variant in HCM cases is incidental. We identified this variant in a HCM proband with no family history of disease or sudden cardiac death. The proband also carries 2 other variants; TNNT2 p.Arg278His and MYH7 c.1000-7C>T. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), the variant does not meet criteria for rarity (PM2) and as a result the identification of the variant in affected probands cannot be used, therefore we classify TNNT2 c.571-7G>A as a variant of 'uncertain significance'.