Submissions for variant NM_001276345.2(TNNT2):c.851+5G>A

dbSNP: rs193922620

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030568	SCV000053239	uncertain significance	not specified	2019-02-05	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.821+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site (ACMG PP3). However, these predictions have yet to be confirmed by functional studies. The variant was absent in 222940 control chromosomes (gnomAD) (ACMG PM2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.821+5G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported in the literature. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic while noting that it has been identified independently of additional cardiogenetic variants in several individuals referred for HCM genetic testing at their laboratory (GeneDx 2016). However, the exact number of functional meiotic transmissions is not specified, therefore, we have not considered this information to support co-segregation within the context of our evaluation at this time. This variant was initially identified in one adult (age >40) male patient referred for a Familial Cardiomyopathy evaluation at our laboratory. However, this patient is lost to follow-up and no information pertaining to clinical history and/or co-segregation with disease is available at this time. Other variants affecting the same canonical splice site (c.821+1G>A, c.821+1G>C and c.821+1G>T) have been reported in association with HCM (HGMD and in the Atlas of Cardiac Genetic Variation database) but that does not unequivocally prove causation for this variant located outside of the canonical splice site in the TNNT2 gene. Therefore, based strictly on the limited information available as outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV000225739	SCV000209265	likely pathogenic	not provided	2019-08-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar by one other clinical laboratory that identified this variant in an adult male referred for Familial Cardiomyopathy evaluation (SCV000053239.2; ClinVar Variant ID#36886; Landrum et al., 2016); +5 splice site variant predicted to destroy the splice donor site of intron 15, the last intron in the TNNT2 gene; functional studies of a different splice variant affecting the same splice donor site (IVS15+1G>A) suggest a likely disease mechanism of aberrant splicing leading to truncated protein(s) (Thierfelder et al., 1994)
Invitae	RCV000804867	SCV000944804	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-11	criteria provided, single submitter	clinical testing	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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 36204818). ClinVar contains an entry for this variant (Variation ID: 36886). 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. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170985	SCV001333650	uncertain significance	Cardiomyopathy	2018-01-05	criteria provided, single submitter	clinical testing