Submissions for variant NM_001276345.2(TNNT2):c.720-4G>T

gnomAD frequency: 0.00009  dbSNP: rs201753429

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036612	SCV000060267	likely benign	not specified	2015-05-07	criteria provided, single submitter	clinical testing	c.690-4G>T in intron 13 of TNNT2: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 14/66732 European chromosomes by the Exome Aggregation Co nsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201753429).
Blueprint Genetics	RCV000208300	SCV000264256	uncertain significance	Sudden cardiac death	2015-10-22	criteria provided, single submitter	clinical testing
Invitae	RCV000468624	SCV000554784	likely benign	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771268	SCV000903390	likely benign	Cardiomyopathy	2018-08-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036612	SCV000920312	uncertain significance	not specified	2018-08-20	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.690-4G>T 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 0.00015 in 277154 control chromosomes in the gnomAD database, including 1 homozygote. Though it is relatively frequent, this frequency is not higher than expected for a pathogenic variant in TNNT2 causing Cardiomyopathy (0.00015 vs 0.00018). c.690-4G>T has been reported in the literature in individuals affected with Cardiomyopathy. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations, including VUS (1x) and likely benign (2x). An internal sample with this variant also carried a pathogenic mutation in MYBPC3 variant (c.2373dupG), suggesting the variant of interest is likely not the cause of disease in this case and may be in the benign spectrum. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneDx	RCV001711103	SCV001942100	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771268	SCV002042852	benign	Cardiomyopathy	2019-06-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001711103	SCV004042461	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	TNNT2: BP4, BS1
PreventionGenetics, part of Exact Sciences	RCV004534773	SCV004752452	likely benign	TNNT2-related disorder	2019-02-22	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Ambry Genetics	RCV004018800	SCV004968980	likely benign	Cardiovascular phenotype	2020-03-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.