ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.302A>G (p.His101Arg) (rs730881087)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159258 SCV000209204 likely pathogenic not provided 2012-02-10 criteria provided, single submitter clinical testing The His101Arg variant in the TNNI3 gene has not been reported previously as a disease-causing mutation or as a rare benign variant, to our knowledge. Although His101Arg results in a conservative amino acid substitution of one positively charged amino acid with another, this position is highly conserved throughout evolution. In silico analysis predicts His101Arg is damaging to the protein structure/function. Also, a mutation in a nearby codon (Ala91Thr) has been reported in association with dilated cardiomyopathy, supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports His101Arg was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The variant is found in DCM,HCM panel(s).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223790 SCV000280505 uncertain significance not specified 2012-02-21 no assertion criteria provided clinical testing 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.

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