ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.842+5G>A (rs193922620)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America 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 2018-05-31 criteria provided, single submitter clinical testing The c.821+5 G>A likely pathogenic variant in the TNNT2 gene has not been reported as pathogenic or benign to our knowledge, and it is not observed in large population cohorts (Lek et al., 2016). This variant has been identified independently of additional cardiogenetic variants in multiple unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. The c.821+5 G>A variant destroys the splice donor site of intron 15, the last intron in the TNNT2 gene, and is predicted to cause aberrant gene splicing. Characterization of a different variant in the splice donor site of intron 15 (c.821+1 G>A) identified two different abnormal mRNA transcripts from the variant allele, both predicted to produce truncated protein products (Thierfelder et al., 1994).
Invitae RCV000804867 SCV000944804 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-12-12 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TNNT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 36886). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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.

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