ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.422G>A (p.Arg141Gln) (rs397516347)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 ( 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 likely pathogenic not provided 2017-09-15 criteria provided, single submitter clinical testing The R141Q likely pathogenic variant has been previously reported in multiple heterozygous individuals from various ethnic backgrounds in association with HCM (Richard et al., 2003; Van Driest et al., 2003; Mogensen et al., 2004; Curila et al., 2009; van den Wijngaard et al., 2011; Rani et al., 2012; Zou et al., 2013; Coppini et al., 2014). Severe and/or early-onset HCM has been reported in an individual homozygous for the R141Q variant (Mogensen et al., 2004), and an individual who harbored R141Q and an additional variant in the MYBPC3 gene (Morita et al., 2008). The R141Q variant is classified as a likely pathogenic variant in ClinVar by at least one other clinical laboratory in association with HCM (ClinVar SCV000059942.4; Landrum et al., 2016), and was found to segregate with HCM in three affected relatives from three separate families (Curila et al., 2009; ClinVar SCV000059942.4; Landrum et al., 2016). This variant has also been observed both independently, and in conjunction with additional cardiogenetic variants, in multiple unrelated individuals referred for HCM genetic testing at GeneDx, although additional informative segregation data is not available. The R141Q variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, R141Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a position where only amino acids with similar properties to Arginine are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, likely pathogenic/pathogenic missense variants at the same residue (R141W) and in nearby residues (R136Q, L144P, R145W, R145Q) have been reported at GeneDx and/or in HGMD in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Invitae RCV000465349 SCV000551896 pathogenic Hypertrophic cardiomyopathy 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 141 of the TNNI3 protein (p.Arg141Gln). 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 several individuals and families from different populations affected with hypertrophic cardiomyopathy (HCM) (PMID: 12707239, 18403758, 23283745, 19645627, 22429680, 25524337, 22876777), including in the homozygous state in an individual that was reported to have very severe disease (PMID: 15607392). ClinVar contains an entry for this variant (Variation ID: 43381). Missense variants that are absent from the ExAC population database have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 27532257). In addition, most of these variants lie within exons 7-8 (PMID: 26440512). A computational algorithm designed to assess the pathogenicity of variants in TNNI3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000777481 SCV000913343 likely pathogenic Cardiomyopathy 2019-03-22 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000777481 SCV001333207 likely pathogenic Cardiomyopathy 2018-06-06 criteria provided, single submitter clinical testing
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).

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