ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.422G>A (p.Arg141Gln)

gnomAD frequency: 0.00004  dbSNP: rs397516347
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000465349 SCV000059942 pathogenic Hypertrophic cardiomyopathy 2019-07-26 criteria provided, single submitter clinical testing The p.Arg141Gln variant in TNNI3 has been reported in >25 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 3 affected relatives from 3 families (Richard 2003, Van Driest 2003, Mogensen 2004, Morita 2008, Curila 2009, van den Wijngaard 2011, Rani 2012, Santos 2012, Kapplinger 2014, Walsh 2017, Invitae pers. comm., LMM data). It was also identified in the homozygous state in an individual with a severe HCM presentation (Mogensen 2004) and in 2 individuals with early-onset HCM who had an additional variant in an HCM-associated gene (MYBPC3, TNNT2) that was likely contributing to disease (Morita 2008, LMM data, Santos 2012). Additionally, this variant has been reported by other clinical laboratories in ClinVar (Variation ID 43381) and has also been identified in 1/8710 of African chromosomes by gnomAD (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Very Strong, PP1, PM2.
GeneDx RCV000159220 SCV000209166 pathogenic not provided 2021-11-15 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15524171, 18227814, 21533915, 24510615, 25351510, 22429680, 12707239, 12860912, 18403758, 19645627, 22876777, 22455086, 23283745, 25524337, 23967088, 27532257, 15607392, 31727422, 31737537, 31447099, 33087929, 34428338, 33673806, 26582918)
Invitae RCV000465349 SCV000551896 pathogenic Hypertrophic cardiomyopathy 2024-01-03 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 141 of the TNNI3 protein (p.Arg141Gln). This variant is present in population databases (rs397516347, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 18403758, 19645627, 22429680, 22876777, 23283745, 25524337). ClinVar contains an entry for this variant (Variation ID: 43381). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000777481 SCV000913343 likely pathogenic Cardiomyopathy 2019-03-22 criteria provided, single submitter clinical testing This missense variant is located in the inhibitory, actin binding region of the TNNI3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in more than ten individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 18403758, 23283745, 19645627, 22429680, 25524337, 22876777), including a homozygous individual who showed a severe phenotype (PMID: 15607392). This variant has been identified in 1/30938 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000777481 SCV001333207 likely pathogenic Cardiomyopathy 2020-03-20 criteria provided, single submitter clinical testing
3billion RCV002051801 SCV002318899 pathogenic Hypertrophic cardiomyopathy 7 2022-03-22 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043381, PMID:12707239). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12707239, 12860912, 18403758, 19645627, 27532257, 26440512). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.982>=0.75). A missense variant is a common mechanism. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0011792). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics RCV002326734 SCV002632086 pathogenic Cardiovascular phenotype 2020-12-11 criteria provided, single submitter clinical testing The p.R141Q pathogenic mutation (also known as c.422G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 422. The arginine at codon 141 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in several individuals with hypertrophic cardiomyopathy (HCM) or from HCM cohorts (Richard P et al. Circulation. 2003;107:2227-32; Van Driest SL et al. Circulation. 2003;108:445-51; van den Wijngaard A et al. Neth Heart J. 2011;19:344-51; Rani DS et al. BMC Med. Genet. 2012;13:69; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Landry CH et al. N Engl J Med. 2017;377(20):1943-1953). This variant was detected in the homozygous state in an individual with severe biventricular hypertrophy (Mogensen J et al. J Am Coll Cardiol. 2004;44:2315-25), and has co-occurred with other variants in cardiac-related genes in affected individuals, including an individual from a childhood-onset HCM cohort (Morita H et al. N Engl J Med. 2008;358:1899-908; Santos S et al. BMC Med Genet. 2012;13:17). This variant has been reported as de novo and shown segregation with disease (Curila K et al. Genet Test Mol Biomarkers. 2009;13:647-50); however, it has also been detected in unaffected relatives (Mogensen J et al. J Am Coll Cardiol. 2004;44:2315-25). Based on internal structural assessment, this alteration disrupts a well-established phosphorylation motif necessary for myofilament Ca2+ sensitivity and ATPase activity (Pi Y et al. J Physiol, 2003 Nov;552:845-57; Wang C et al. Structure, 2012 May;20:791-801). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics RCV002477081 SCV002789029 pathogenic Dilated cardiomyopathy 2A; Cardiomyopathy, familial restrictive, 1; Dilated cardiomyopathy 1FF; Hypertrophic cardiomyopathy 7 2021-07-28 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV002477081 SCV003920895 likely pathogenic Dilated cardiomyopathy 2A; Cardiomyopathy, familial restrictive, 1; Dilated cardiomyopathy 1FF; Hypertrophic cardiomyopathy 7 2021-03-30 criteria provided, single submitter clinical testing TNNI3 NM_000363.4 exon 7 p.Arg141Gln (c.422G>A): This variant has been reported in the literature in several individuals with HCM, including once in the homozygous state (Richard 2003 PMID:12707239, Van Driest 2003 PMID:12860912, Morgensen 2004 PMID:15607392, Santos 2012 PMID:22429680, Rani 2012 PMID:22876777, Ramachandran 2013 PMID:23967088, Walsh 2017 PMID:27532257). This variant also segregated with disease in one family (Curila 2009 PMID:19645627). This variant is present in 0.003% (1/31370) of total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-55665525-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, and/or variable expressivity. This variant is also present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:43381). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000159220 SCV000280506 likely pathogenic not provided 2014-12-12 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.Arg141Gln (c.422 G>A) in the TNNI3 gene (NM_000363.4). Given the strong case data and absence in the general population (reviewed below) we consider this variant likely disease causing. The variant has been seen in at least 11 unrelated cases of HCM (not including this patient's family). There is only weak segregation data available from one family. Richard et al (2003) observed the variant in one patient with HCM from their 197 patient French cohort that underwent sequencing of multiple sarcomere genes. van Driest et al (2003) observed the variant in one patient with HCM from their 389 patient cohort recruited at Mayo. He was diagnosed at 27 years of age. Mogenson et al (2004) observed the variant in two HCM patients from their cohort of 748 HCM patients cared for by Bill McKenna's group at St. George's hospital in London. One patient was actually homozygous for the variant. That patient was noted to have a particularly severe presentation with biventricular hypertrophy. Family members were not available to be evaluated but there was concerning family history. Morita et al (2008) observed the variant in one HCM patient in a cohort of 84 pediatric HCM cases from the pediatric cardiomyopathy registry (recruited throughout North America). The patient also carried p.Arg495Gln in MYBPC3 (we have reviewed this variant and classify it as likely disease causing). Individual phenotypic details were not available (though onset was pediatric in all cases). Rani et al (2012) sequenced just TNNI3 in 101 patients with HCM from their South Indian cohort and observed this variant in two patients. They do not explicitly state that the patients were all unrelated, though presumably they were. Santos et al (2012) observed the variant in one HCM patient from their Portuguese cohort of 80 HCM patients. Curila et al (2009) observed the variant in 2 patients with HCM in their Czech cohort of 101 HCM patients. In one family it segregated with disease in 2 affected first degree relatives. van den Wijngaard et al (2011) observed the variant in a patient with HCM from a large cohort of 1040 HCM patients pooled from clinics across the Netherlands. Ramachandran et al (2013) studied this variant in silico and found it altered local protein structure and changed intra and intermolecular hydrogen bonding patterns. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (score 0.975) and SIFT predicts it to be deleterious. The Grantham score is 43. The arginine at codon 141 is completely conserved across mammals, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (Arg145Gln, Arg145Gly, Arg144Gln, Arg144Pro). I could not find another variant at the same codon. The variant falls in the troponin C binding domain. Of note, there are a lot of variants in patients in this region but none to few in general population samples like NHLBI ESP. In total the variant has not been seen in 7310 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 141 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of April 8th, 2014). There is also no variation at this codon listed in dbSNP (as of April 8th, 2014). The variant was not observed in the following laboratory and published control samples: 200 healthy individuals analyzed by GeneDx, 100 healthy individuals (Richard et al 2003), 200 healthy individuals (van Driest et al 2003), 160 healthy individuals from South India (Deepa et al 2012), 150 healthy individuals (Mogenson et al 2004).
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000159220 SCV001930066 likely pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000159220 SCV001956803 pathogenic not provided no assertion criteria provided clinical testing
Institute of Human Genetics, University of Wuerzburg RCV000777481 SCV003804384 likely pathogenic Cardiomyopathy no assertion criteria provided clinical testing

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