Submissions for variant NM_001276345.2(TNNT2):c.375del (p.Glu126fs)

dbSNP: rs560019679

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000809932	SCV000950115	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-07-08	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. This sequence change creates a premature translational stop signal (p.Glu116Argfs*66) in the TNNT2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNT2 cause disease. This variant is not present in population databases (gnomAD no frequency). 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: 654045).
Color Diagnostics, LLC DBA Color Health	RCV001175721	SCV001339431	uncertain significance	Cardiomyopathy	2023-07-25	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 9 of the TNNT2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 30847666, 34008892). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TNNT2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729708	SCV001976711	likely pathogenic	Dilated cardiomyopathy 1D	2021-10-01	criteria provided, single submitter	clinical testing	PVS1, PM2, PP3
AiLife Diagnostics, AiLife Diagnostics	RCV002223948	SCV002502390	uncertain significance	not provided	2021-09-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003307498	SCV004001495	uncertain significance	Cardiovascular phenotype	2023-04-10	criteria provided, single submitter	clinical testing	The c.345delA variant, located in coding exon 8 of the TNNT2 gene, results from a deletion of one nucleotide at nucleotide position 345, causing a translational frameshift with a predicted alternate stop codon (p.E116Rfs*66). This variant (also referred to as c.375delA, p.Glu126Argfs*66) has been detected in an individual referred for dilated cardiomyopathy genetic testing and in an individual with phenylketonuria and cardiomyopathy; however, details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Marinakis NM et al. Am J Med Genet A, 2021 Aug;185:2561-2571). This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of TNNT2 has not been established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001175721	SCV004829710	uncertain significance	Cardiomyopathy	2023-08-08	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 9 of the TNNT2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 30847666, 34008892). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TNNT2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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.