ClinVar

Description

Variant summary: TNNC1 c.23C>T (p.Ala8Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. As this variant is located in the exonic splice region close to the canonical intronic splice donor site, several computational tools predict a conflicting impact on normal splicing: One predicts no significant impact on splicing. One predicts the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 1585600 control chromosomes (gnomAD v4.0). This frequency is not significantly higher than estimated for a pathogenic variant in TNNC1 causing Cardiomyopathy (1.3e-05 vs 2.5e-05), allowing no conclusion about variant significance. c.23C>T has been reported in the literature in individuals affected with Cardiomyopathy (eg. Landstrom_2008, Bos_2014, Jaafar_2015, Martins_2015, Ploski_2016, Jaaskelainen_2019, Mademont-Soler_2017, van Lint_2019, etc). The only segregation data reported by these studies was the observation of the variant in two siblings with infantile onset restrictive cardiomyopathy who were compound heterozygous with a second variant in TNNC1, and both heterozygous parents were asymptomatic (Ploski_2016). These data indicate that the variant is very likely to be associated with disease. There have been a variety of in vitro functional studies reported on this variant which suggest the variant impacts the function of the Troponin C protein, but the observed effects were varied and the physiological relevance of those effects in humans is unclear (eg. Landstrom_2008). Additionally, a mouse model with this variant was shown to recapitulate aspects of human HCM, further suggesting a functional impact of the variant (Martins_TNNC1_CCG_2015). The following publications have been ascertained in the context of this evaluation (PMID: 24793961, 26779504, 30775854, 18572189, 28771489, 26304555, 27604170, 30847666). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (P/LP, n=9 ; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.