ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.557G>A (p.Arg186Gln) (rs397516357)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000167988 SCV000059958 pathogenic Hypertrophic cardiomyopathy 2018-03-19 criteria provided, single submitter clinical testing The p.Arg186Gln variant in TNNI3 has been identified in at least 14 individuals with HCM, segregated with disease in 14 affected relatives from 4 families (Rich ard 2004, Mogensen 2004, Millat 2010, Fokstuen 2011, Zhu Hu 2012, Roberts 2013, Wang 2015, Walsh 2016, LMM data). It was absent from large population studies. I n summary, this variant meets our criteria to be classified as pathogenic for HC M in an autosomal dominant manner based upon case observations, segregation stud ies and absence from controls. ACMG/AMP Criteria applied: PS4; PP1_Strong; PM2; BP4.
GeneDx RCV000223924 SCV000209185 pathogenic not provided 2018-04-13 criteria provided, single submitter clinical testing The R186Q variant in the TNNI3 gene has been reported several times in association with cardiomyopathy (Richard et al., 2003; Mogensen et al., 2004; Moon et al., 2005; Millat et al., 2010; Fokstuen et al., 2011; Zhu et al., 2012; Roberts et al., 2013; Coppini et al., 2014; Wang et al, 2015; Walsh et al., 2017). This variant has also been reported to segregate with disease in over ten individuals from multiple unrelated families (Morgensen et al., 2004; Roberts et al., 2013; Wang et al., 2015). Furthermore, this variant has been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx, and segregated with a cardiomyopathy phenotype in at least one family, in the absence of any other disease-causing variants. The R186Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, the R186Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis suggests that this variant is damaging to the protein structure/function.
Invitae RCV000167988 SCV000218638 pathogenic Hypertrophic cardiomyopathy 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 186 of the TNNI3 protein (p.Arg186Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in multiple unrelated individuals with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 20624503, 25524337, 21239446, 27532257) and has been shown to segregate with cardiomyopathy phenotypes in two additional families (PMID: 15607392, 23540544). ClinVar contains an entry for this variant (Variation ID: 43395). Missense variants that are absent from the ExAC population database have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000620207 SCV000736237 pathogenic Cardiovascular phenotype 2019-03-11 criteria provided, single submitter clinical testing The p.R186Q pathogenic mutation (also known as c.557G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 557. The arginine at codon 186 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) in multiple individuals (Richard P, Circulation 2003 May; 107(17):2227-32; Millat G, Eur J Med Genet 2010; 53(5):261-7; Roberts WC, Am. J. Cardiol. 2013 Jun; 111(12):1818-22; Lopes LR, Heart 2015 Feb; 101(4):294-301). In addition, this alteration has been shown to segregate with disease across two families (Mogensen J, J. Am. Coll. Cardiol. 2004 Dec; 44(12):2315-25; Wang C, Mol. Genet. Genomics 2016 Feb; 291(1):79-92). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000157533 SCV000740429 likely pathogenic Primary familial hypertrophic cardiomyopathy 2016-07-29 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000167988 SCV000886795 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770565 SCV000902014 pathogenic Cardiomyopathy 2016-07-07 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258033 SCV001434861 pathogenic Familial hypertrophic cardiomyopathy 7 2019-01-17 criteria provided, single submitter clinical testing The c.557G>A (p.Arg186Gln) variant in the TNNI3 gene has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 22301726, 23540544, 25524337, 25351510, 26169204, 27532257). This variant is not observed in gnomAD. This variant has been reported to co-segregate with HCM in multiple families with incomplete penetrance (PMID: 15607392, 23540544). This variant has also been reported in patients with HCM by other laboratories. The Arginine 186 is a moderately conserved residue, and multiple algorithms predicted the p.Arg186Gln change to be deleterious. Therefore, the c.557G>A (p.Arg186Gln) variant in the TNNI3 gene is classified as pathogenic.
Blueprint Genetics RCV000157533 SCV000207279 pathogenic Primary familial hypertrophic cardiomyopathy 2014-05-13 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223924 SCV000280512 pathogenic not provided 2011-03-01 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. The patient had HCM genetic testing with the GeneDx laboratory. The test included sequencing of 18 genes associated with HCM: MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC, MYL3, MYL2, LAMP2, PRKAG2, GLA, CAV3, MTTG, MTTI, MTTK, MTTQ, TTR, and TNNC1. Results reported on Nov 23rd 2010 showed that a variant associated with disease was identified: p.Arg186Gln (c.557G>A) in the TNNI3 gene. This variant has been reported in multiple cases of HCM. Richard et al (2003) found the p.Arg186Gln variant in one individual with HCM. No segregation data was reported. Mogensen et al (2004) observed the variant in two unrelated families with HCM. Segregation data was not reported separately for each family, however of 11 total genotype positive individuals in both families, 5 had HCM. No other variants have been reported at codon 186, however a variant has been reported with HCM at a nearby codon (p. Lys183Glu (Mogensen et al 2004)). Arginine is highly conserved across species and isoforms at position 186. This variant substitutes a polar, positively charged amino acid (Arg) with a polar, neutral amino acid (Gln). Richard et al (2003) did not identify the variant in 100 presumably healthy controls of unspecified ethnicity and Mogenson et al (2004) did not observe it in 75 presumably healthy individuals, for a total of 175 controls. Based on these data it is very likely that this variant causes cardiomyopathy.

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