ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.235C>T (p.Arg79Cys) (rs3729712)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036275 SCV000059927 benign not specified 2017-11-22 criteria provided, single submitter clinical testing p.Arg79Cys in exon 5 of TNNI3: This variant is not expected to have clinical sig nificance because it has been identified in 0.6% (115/18670) of East Asian chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs3729712). BA1
GeneDx RCV000036275 SCV000209157 likely benign not specified 2017-06-12 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000253834 SCV000319767 benign Cardiovascular phenotype 2019-03-20 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV000464815 SCV000562162 likely benign Hypertrophic cardiomyopathy 2020-11-25 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000721099 SCV000987480 likely benign not provided criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000464815 SCV000995486 likely benign Hypertrophic cardiomyopathy 2018-05-08 criteria provided, single submitter clinical testing
Mendelics RCV000991060 SCV001142165 benign Familial hypertrophic cardiomyopathy 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001135029 SCV001294795 likely benign Familial restrictive cardiomyopathy 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001135030 SCV001294796 uncertain significance Dilated cardiomyopathy 2A 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001135031 SCV001294797 likely benign Familial hypertrophic cardiomyopathy 7 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001135032 SCV001294798 likely benign Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170622 SCV001333213 benign Cardiomyopathy 2018-07-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV001170622 SCV001339283 benign Cardiomyopathy 2018-10-11 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000721099 SCV000280498 likely benign not provided 2017-09-06 no assertion criteria provided provider interpretation p.Arg79Cys (c.235C>T) in the TNNI3 gene. Given the frequency (0.1%) in Asian individuals unselected for HCM and the failure to segregate, we consider this variant likely benign, with potential to be a modifier. The variant has been seen in at least 6 unrelated cases of HCM (not including this patient's family). The p.Arg79Cys variant in TNNI3 was first reported by Kimura et al (1997) as a polymorphism in five unrelated patients with HCM and in healthy control individuals (detailed control data not provided). This cohort is likely of East Asian descent as the study was conducted in Japan. It was also noted the p.Arg79Cys variant did not segregate with cardiomyopathy in these five families. Subsequently, Mogensen et al. (2004) reported the p.Arg79Cys variant in an individual of Asian decent with HCM and considered it a polymorphism based on the previous report by Kimura et al. Segregation analysis was not performed in this family. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging to the protein structure/function and mutationtaster predicts it to be disease-causing. The p.Arg79Cys variant at codon 79 is conserved across mammals, but not in x tropicalis (western clawed frog). Other variants have been reported in the Human Gene Mutation Database in association with disease at nearby codons (p.Arg74Pro, p.Pro82Ser) in association with cardiomyopathy (Stenson et al., 2009). In total the variant has been seen in 50 of ~53,696 published controls and individuals from publicly available population datasets. This variant is listed in dbSNP and 1000 genomes (rs3729712, as of 01/21/2015). The variant was observed in the following published control samples: Murakami et al. (2010) reported the p.Arg79Cys variant in 2 controls in a cohort that is likely of Asian ancestry. Kapplinger et al. (2014) also reported the variant in 2 individuals of a control cohort of 427 individuals of various ethnic backgrounds. The variant was reported online in 46 of 53,269 individuals in the Exome Aggregation Consortium dataset (http//exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 01/21/2015). Specifically, the variant was observed in 43 of 4026 individuals (0.1%) of the East Asian ancestry. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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