ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.484C>T (p.Arg162Trp) (rs368861241)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000475238 SCV000203864 likely pathogenic Hypertrophic cardiomyopathy 2017-09-08 criteria provided, single submitter clinical testing The p.Arg162Trp variant in TNNI3 has been reported in the heterozygous state in >5 individuals with HCM (Kimura 1997, Garcia-Pavia 2011, Kubo 2011, Santos 2012, LMM data). It was also identified in the homozygous state in 1 Indian and 1 Jor danian individual with HCM and segregated with disease in the homozygous state i n 3 affected relatives, but none of the heterozygous relatives were affected (G ray 2013, Das 2014, LMM data). The variant has been identified in 3/111,610 Euro pean chromosomes and 3/30,779 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs368861241). In vitr o functional studies provide some evidence that the p.Arg162Trp variant may impa ct protein function (Elliott 2000, Takahashi-Yanaga 2001). However, these types of assays may not accurately represent biological function. Computational predic tion tools and conservation analysis do not provide strong support for or agains t an impact to the protein. However, two other likely pathogenic variants have b een identified at this position (p.Arg162Pro, p.Arg162Gln), suggesting changes a t this position are not tolerated. The available data on the p.Arg162Gln suggest s that it may be a mild variant, with reduced penetrance. In summary, the p.Arg1 62Trp variant is likely pathogenic; however, this variant may have a milder role suggested by the incomplete penetrance seen in some family members and the indi viduals who were homozygous, similar to that observed for p.Arg162Gln. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PM5_Strong, PP1.
GeneDx RCV000159228 SCV000209174 pathogenic not provided 2017-02-02 criteria provided, single submitter clinical testing The R162W pathogenic variant in the TNNI3 gene has been reported in association with HCM (Kimura et al., 1997; Elliott et al., 2000; Xu et al., 2010; Hirota et al., 2010; Garcia-Pavia et al., 2011; Kubo et al., 2011; Santos et al., 2012). Gray et al. (2013) reported siblings homozygous for this variant in which the proband had HCM with features of a restrictive process and her brother had classic HCM. In that family, autosomal recessive inheritance was proposed as the four individuals heterozygous for the variant (both parents and two siblings) were clinically unaffected. Possible autosomal recessive inheritance of this variant was also observed in two unrelated families by another clinical lab; however, that lab classified this variant as of uncertain significance (SCV000203864.3, Landrum et al., 2016). The R162W pathogenic variant has been observed in multiple other unrelated individuals tested for HCM at GeneDx, including one individual with restrictive cardiomyopathy in whom the variant was apparently homozygous. The R162W variant was not observed with any significant frequency 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 those populations. Considering all publications cited above, the R162W variant was also absent from 658 control individuals. The R162W variant is a non-conservative amino acid substitution. As these residues differ in polarity, charge, size and/or other properties, it is more likely to impact secondary structure. Arginine is conserved at this position in mammals and in silico analysis predicts this substitution is likely to be damaging to protein structure/function. In vitro functional studies demonstrate that R162W interferes with normal troponin function and is expected to impair cardiac muscle relaxation (Elliott et al., 2000; Takahashi-Yanaga et al., 2001). Furthermore, other pathogenic missense variants at the same residue (R162Q, R162P), as well as in nearby residues (A157V, K164T, S166F), have been reported in association with HCM, further supporting the functional importance of this residue and region of the protein (Stenson et al., 2014). In summary, R162W in the TNNI3 gene is interpreted as a pathogenic variant
Invitae RCV000475238 SCV000551900 likely pathogenic Hypertrophic cardiomyopathy 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 162 of the TNNI3 protein (p.Arg162Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs368861241, ExAC 0.01%). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 21799269, 21896538, 22429680, 27532257, 28356264, 25132132). This variant has also been observed in the homozygous state in two siblings with hypertrophic cardiomyopathy and heterozygous carriers did not show a phenotype in this family (PMID: 24113344). ClinVar contains an entry for this variant (Variation ID: 161396). This variant has been reported to affect TNNI3 protein function (PMID: 10806205, 11735257). This variant disrupts the p.Arg162 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been observed in individuals with TNNI3-related conditions (PMID: 15607392, 22876777, 15698845, 15992656, 16352453), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000722122 SCV000696595 likely pathogenic Cardiovascular phenotype 2018-07-27 criteria provided, single submitter clinical testing Variant summary: TNNI3 c.484C>T (p.Arg162Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function and a different missense mutation at this same residue (p.Arg162Gln) has been internally classified as Likely Pathogenic, suggesting that changes at Arg162 are not tolerated. Additionally, several functional studies indicate that this variant reduces the apparent affinity of cTnI for actin without changing the intrinsic inhibitory activity, and induces a definite increase in the Ca2+- sensitivitiy of myofibrillar ATPase activity and force generation in skinned muscle fibers. It has been suggested that the decreased inhibition and increased calcium sensitivity may cause HCM via impaired relaxation rather than the impaired contraction seen with some other classes of HCM mutants (Elliott_2000). The variant allele was found at a frequency of 4e-05 in 247390 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in LMM reportedly detected the variant in 4 individuals with HCM (1 Caucasian adult, 2 Indian adolescents, and 1 Jordanian adolescent). Several reported HCM patients in the literature (Kimura_1997, Garcia-Pavia_ 2011, Wang_2014, etc), and two individuals reported by LMM laboratory, were all heterozygous for the variant of interest, which is consistent with dominant inheritance. However, the variant has also been reported in two non-Caucasian families (one Indian and one Jordanian reported by LMM) and one Middle Eastern family (Gray_TNNI3_Int J Cardiol_2013) with 5 affected individuals being homozygous from the 3 families and none of the heterozygous family members being affected. This may suggest that c.484C>T is either a mild variant with reduced penetrance, and/or co-dominant effect is required to develop clinical features; recessive mode of inheritance cannot be completely ruled out. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709765 SCV000840074 pathogenic Familial hypertrophic cardiomyopathy 7 2018-01-30 criteria provided, single submitter clinical testing This c.484C>T (p.Arg162Trp) variant in the TNNI3 gene has been reported in multiple HCM patients with significantly higher prevalence [PMID: 9241277,21799269,21896538,22429680] than that observed as extremely low in general population according to gnomad database. Arginine at amino acid position 162 is highly conserved during evolution. Other amino acid changes at this or nearby positions have been reported in HCM patients as deleterious mutations [PMID: 27385602, 12860912, 21310275, 25611685, 27532257]. Functional studies showed that this mutant causes increased calcium sensitivity of cardiac muscle contraction and other alterations [PMID: 11735257, 10806205]. Homozygotes of this variant have been observed in two affected siblings with HCM while heterozygous carriers in this family are all normal. Multiple in silico predictions suggest this arginine to histidine change is deleterious. Based upon above evidences, this c.484C>T (p.Arg162Trp) variant in the TNNI3 gene is classified as pathogenic.
CSER_CC_NCGL; University of Washington Medical Center RCV000148896 SCV000190642 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.