Submissions for variant NM_001276345.2(TNNT2):c.720-6G>A

gnomAD frequency: 0.00002  dbSNP: rs113471285

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017310	SCV000060268	uncertain significance	not provided	2023-02-07	criteria provided, single submitter	clinical testing	The c.690-6G>A variant in TNNT2 has been identified in 2 individuals with dilated cardiomyopathy (DCM) who also carried a potentially disease-causing variant in TNNT2, which was confirmed in cis in one of these individuals, as well as 1 individual with hypertrophic cardiomyopathy (HCM; Morales 2010 PMID: 20973921, Ntusi 2016 PMID: 27841901, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43665) and has been identified in 0.00065% (1/15284) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.2.1). This variant is located in the 3' splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP2, PM2_Supporting.
GeneDx	RCV000036613	SCV000514926	benign	not specified	2015-05-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV001099020	SCV001255428	uncertain significance	Hypertrophic cardiomyopathy 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001099021	SCV001255429	uncertain significance	Dilated cardiomyopathy 1D	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001099022	SCV001255430	uncertain significance	Cardiomyopathy, familial restrictive, 3	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001192357	SCV001360407	likely benign	Cardiomyopathy	2019-10-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036613	SCV001362089	uncertain significance	not specified	2019-11-19	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.690-6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251442 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.690-6G>A has been reported in the literature in individuals affected with dilated- and hypertrophic cardiomyopathy (Morales_2010, Pugh_2014). These reports however, do not provide unequivocal conclusions about association of the variant with the disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as benign (1x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae	RCV001426925	SCV001629588	likely benign	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-09-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001192357	SCV004823267	likely benign	Cardiomyopathy	2024-01-03	criteria provided, single submitter	clinical testing