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.Pro54His (P54H; c.161 C>A) in the TNNC1 gene. This variant is completely novel, and has not been previously reported as a disease-causing mutation or as a benign polymorphism. Variation at nearby residues in TNNC1 has been associated with cardiomyopathy, potentially supporting the functional importance of this region of the protein: Gln50Arg, Glu59Asp (HGMD via GeneDx). This is a non-conservative amino acid change, resulting in the replacement of a nonpolar proline with a positively-charged histidine. The proline at this location is highly conserved across 43 vertebrate species, differing only in tree shrew (lysine) and megabat (threonine). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.970. GeneDx reports that its in silico analysis (programs not named) predicts the change to be “possibly damaging”. In total this variant has not been seen in ~6500 individuals from publicly available population datasets. Not many of these individuals are ancestry-matched with our patient, however. (Our patient has Afghani ancestry.) No variation at this codon is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 2/7/2013). No variation at this codon is present in dbSNP or in 1000 genomes. GeneDx did not report additional controls.