ClinVar

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ala8Val (c. 23 C>T) in TNNC1 Given the lack of case data and the somewhat tenuous link between HCM and TNNC1, we classify it as a variant of uncertain significance. This variant has been reported in one individual with HCM; he was diagnosed at 33 and had no family history of SCD or HCM (Landstrom et al 2008). To the best of our knowledge there are no other published reports of this variant in HCM. There is also no segregation data available on this variant. Only a handful of variants in TNNC1 have been reported in association with HCM and some groups question whether there is sufficient evidence supporting the link between HCM and TNNC1. Interestingly, from the paper that first reported this variant we are able to get data on the prevalence of TNNC1 variants in patients with HCM, which we can then compare to the prevalence of such variants in the general population. Landstrom et al (2008) sequenced TNNC1 in 1025 patients with HCM and identified rare missense variants (including this one) in 4 individuals (i.e. ~0.4%). Of note, in a general population sample, 0.1% of individuals had a rare or unique missense variant in TNNC1 (from the NHLBI ESP data set). Landstrom et al (2008) showed that specific missense mutations occurring in TNNC1, including this p.Ala8Val variant, show increased Ca2+ sensitivity of force development and force recovery. However, a subsequent paper from the same group noted that this variant was associated with diminished Ca2+ sensitivity (Pinto et al 2009). Swindle et al (2010) reported that p.Ala8Val did not affect the calcium or magnesium binding properties of the C-domain and it had no effects on binding of troponin C to troponin I. This variant occurs in the N-helix of the amino acid-terminal domain of the protein. The Alanine at codon 8 is completely conserved (Landstrom et al 2008). PolyPhen2 predicts the variant to be possibly damaging. It is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5,300 Caucasian and African American individuals (as of May 2012). It is also not currently listed in dbSNP or 1000 genomes (as of May 2012). Landstrom et al (2008) did not observe the variant in 500 general population samples. p. Asp464Asn (c. 1390 G>A) in PRKAG2 Genetic testing also identified another variant of unknown significance in the PRKAG2 gene, Asp464Asn (c. 1390 G>A). This variant is novel. This results in a non-conservative amino acid change, where a negatively-charged amino acid (Aspartic Acid) is changed to a neutral, polar amino acid (Asparagine). This variant is predicted to be benign by PolyPhen-2 analysis. This residue is conserved across species. No other disease-causing variants have been reported at this or nearby codons. The variant was not observed in 313 individuals of various ethnic backgrounds at GeneDx. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5,000 Caucasian and African American individuals (as of May 2012). The variant is not listed in dbSNP or 1000 genomes (as of May 2012).