Submissions for variant NM_001276345.2(TNNT2):c.852-2A>C

dbSNP: rs111692981

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484808	SCV000566974	pathogenic	not provided	2015-06-19	criteria provided, single submitter	clinical testing	Although the c.822-2 A>C substitution has not been reported as a pathogenic variant or as a benignpolymorphism to our knowledge, this variant destroys the canonical splice acceptor site in intron 15 and ispredicted to cause abnormal gene splicing. The variant is predicted to lead to either an abnormal messagethat is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message isused for protein translation. Other splice site variants in the TNNT2 gene have been reported in HGMDin association with cardiomyopathy (Stenson P et al., 2014). In summary, c.822-2 A>C in the TNNT2 gene is interpreted as a pathogenic variant.
Ambry Genetics	RCV000618372	SCV000740250	uncertain significance	Cardiovascular phenotype	2017-11-28	criteria provided, single submitter	clinical testing	The c.822-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 16 in the TNNT2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of TNNT2 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526539	SCV003235513	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2022-09-14	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 15 of the TNNT2 gene. It does not directly change the encoded amino acid sequence of the TNNT2 protein. It affects a nucleotide within the consensus splice site. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 419277).