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

gnomAD frequency: 0.00048  dbSNP: rs3729712

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	RCV000721099	SCV000209157	likely benign	not provided	2019-11-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24510615, 15607392, 26506446, 21310275, 9241277, 32815737, 33078954)
Ambry Genetics	RCV000253834	SCV000319767	benign	Cardiovascular phenotype	2019-03-20	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000464815	SCV000562162	likely benign	Hypertrophic cardiomyopathy	2024-01-26	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	Hypertrophic cardiomyopathy 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001135029	SCV001294795	likely benign	Cardiomyopathy, familial restrictive, 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 Laboratory Services, 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 Laboratory Services, Illumina	RCV001135031	SCV001294797	likely benign	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 Laboratory Services, 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 Diagnostics, LLC DBA Color Health	RCV001170622	SCV001339283	benign	Cardiomyopathy	2018-10-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000721099	SCV004564544	likely benign	not provided	2023-10-18	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000721099	SCV001932501	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000721099	SCV001951550	likely benign	not provided		no assertion criteria provided	clinical testing