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.His101Arg (H101R; c.302 A>G). To our knowledge, the His101Arg variant has not previously been reported either as a disease-causing variant or as a benign rare variant. A variant at a nearby codon of TNNI3 (within 10 amino acids to either side) has been associated with disease, which may support the functional importance of this region of the protein. Specifically, Ala91Thr has been associated with dilated cardiomyopathy in an Asian Indian patient (Boda et al. 2009). The patient was a 6-year-old girl with 30% EF, mild mitral regurgitation, and a family history of sudden cardiac deaths. His101Arg is a conservative amino acid change from a positively-charged Histidine to a positively-charged Arginine. However, the Histidine at codon 101 is absolutely conserved across 31 vertebrate species examined. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. The testing lab reports that Mutation Taster also predicts the variant to be damaging to protein structure/function. In total the variant has not been seen in ~5100 individuals from publicly available population datasets. There is no amino acid variation at codon 101 listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~3400 Caucasian and ~1700 African American individuals (the patient’s ancestry is Caucasian, Mexican, and Basque). There is no variation at this codon listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or in 1000 genomes (http://browser.1000genomes.org/index.htm) as of 2/21/2012.