rs368861241
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP3_ModeratePP5
The NM_000363.5(TNNI3):c.484C>T(p.Arg162Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,612,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R162P) has been classified as Pathogenic.
Frequency
Consequence
NM_000363.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000659 AC: 1AN: 151844Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000402 AC: 10AN: 249000Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135190
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1460962Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 726840
GnomAD4 genome 0.00000659 AC: 1AN: 151844Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74126
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 7 Pathogenic:5Uncertain:2
PM2_Supporting+PS4_Moderate+PS3_Supporting+PM1 -
- -
- -
The heterozygous p.Arg162Trp variant in TNNI3 was identified by our study in one individual with hypertrophic cardiomyopathy. This variant has been identified in 0.004071% (10/245660) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368861241). Please note that for diseases like hypertrophic cardiomyopathy with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has been reported likely pathogenic or pathogenic in ClinVar (Variation ID: 161396). Two additional missense variants that affect the Arginine (Arg) at position 162 have been reported likely pathogenic or pathogenic in ClinVar, suggesting that a change in this position would not be tolerated (Variation ID: 43390, 43389). The p.Arg162Trp variant in TNNI3 has been reported in 12 individuals (6 Middle Eastern, 6 unknown) and segregated with disease in the homozygous state in 4 affected relatives from 2 families. The 6 clinically unaffected individuals from these 2 families were heterozygous for the variant, though this disease is known to have clinical variability (PMID: 24113344, 23270746). Four additional, unrelated individuals with this variant and hypertrophic cardiomyopathy have been reported in the literature (PMID: 22429680, 21799269). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that the p.Arg162Trp variant may impact protein function by reducing inhibition of actin-tropomyosin-activated myosin ATPase and increased calcium sensitivity in enzyme activity regulation (PMID: 11735257, 10806205). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP1, PP3, PM2, PM5, PS3_Supporting (Richards 2015). -
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. -
The variant NM_000363.5(TNNI3):c.484C>T, p.(Arg162Trp) has been assessed using the ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TNNI3 Version 1.0.0 Based on this information, the following ACMG/AMP criteria were applied in classifying this variant: PM1 -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 3A-VUS. Following criteria are met: 0103 - Both loss-of function and gain-of-function are known mechanisms of disease for this gene and are associated with hypertrophic cardiomyopathy 7 (HCM; MIM#613690). Missense have variants been functionally proven to cause both mechanisms (PMID: 21533915). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. The recessive form of inheritance is the exception and has only been reported in two families (PMIDs: 15070570, 23270746). (I) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 15607392). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 23270746). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (10 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (10 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated troponin domain (NCBI, PDB, DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Three alternative changes in this same residue, p.(Arg162Pro), p.(Arg162Gln) and p.(Arg162Leu), have been reported in multiple individuals with HCM (ClinVar, PMID: 32686758). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. Even though there are reports in the literature that classify this variant as a variant of uncertain significance (VUS) (DECIPHER, PMID: 27532257), it has been reported as likely pathogenic and pathogenic in multiple individuals with HCM (ClinVar, PMIDs: 32830170, 32686758, 28420666). It has also been reported in families with autosomal recessive inheritance, with unaffected heterozygote carriers (ClinVar, PMID: 23270746). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies show that mutant reduced ability to inhibit actin-TM-activated myosin ATPase and increased calcium sensitivity of ATPase regulation, suggesting that this mutation may result in relaxation abnormalities rather than contraction as other mutants reported in HCM. In addition, the mutant has an increased affinity for TnC (PMID: 10806205). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Hypertrophic cardiomyopathy Pathogenic:5
TNNI3 p.Arg162Trp was identified as a homozygous variant in 1 HCM proband as part of our research program. The proband came from a consanguineous family of Middle Eastern descent. An affected sibling was also found to have this homozygous variant. For further information please feel free to contact us. -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the TNNI3 protein (p.Arg162Trp). This variant is present in population databases (rs368861241, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy, in the heterozygous and homozygous states (PMID: 9241277, 21799269, 21896538, 22429680, 25132132, 27532257, 28356264, 30847666, 32746448, 33673806). ClinVar contains an entry for this variant (Variation ID: 161396). 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. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 10806205, 11735257). This variant disrupts the p.Arg162 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12860912, 15607392, 15698845, 15992656, 16352453, 22876777). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
This missense variant replaces arginine with tryptophan at codon 162 of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant increases the Ca2+ sensitivity of cardiac muscle contraction (PMID: 10806205, 11735257). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 21799269, 21896538, 22429680, 24113344, 27532257, 30105547, 30847666, 32746448, 33495596, 33495597, 33673806). In one family, this variant was observed in homozygosity in two siblings affected with hypertrophic cardiomyopathy (PMID: 24113344). However, four heterozygous carriers from this family were not clinically affected. This variant has been identified in 10/249000 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at this codon, p.Arg162Pro and p.Arg162Gln, are considered to be disease-causing (ClinVar variant ID: 43390 and 43389), suggesting that arginine at this position is important for TNNI3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
The c.484C>T (p.Arg162Trp) variant in the TNNI3 gene is located on the exon 7 and is predicted to replace arginine with tryptophan at codon 162 (p.Arg162Trp). The variant has been reported in more than 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 30105547, 32830170, 21799269, 9241277, 21896538, 28356264, 22429680, 27532257, 23270746). Alternative variants disrupting the same amino acid (p.Arg162Gln, p.Arg162Pro) have been interpreted as likely pathogenic or pathogenic in ClinVar (ID: 43389, 43390). In vitro experimental studies show evidence for a negative functional impact of the p.Arg162Trp variant (PMID: 10806205, 11735257). This variant is rare in the general population according to gnomAD (10/249000). Therefore, the c.484C>T (p.Arg162Trp) variant of TNNI3 has been classified as likely pathogenic. -
The p.Arg162Trp variant in TNNI3 has been reported in the heterozygous state in >10 individuals with hypertrophic cardiomyopathy (HCM; Kimura 1997 PMID: 9241277; Garcia-Pavia 2011 PMID: 21896538; Kubo 2011 PMID: 21799269; Gomez 2017 PMID: 28356264; Walsh 2017 PMID: 27532257; LMM data). It was also identified in the homozygous state in 1 Indian and 1 Jordanian individuals with HCM and segregated with disease in the homozygous state in 3 affected relatives, but none of the heterozygous relatives (<50 years old) were affected (Gray 2013 PMID: 23270746; Das 2014 PMID: 24113344; LMM data). The variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 161396) and was identified in 0.003% (3/113182) of European chromosomes and 0.02% (3/17978) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg162Trp variant may impact protein function (Elliott 2000 PMID: 10806205; Takahashi-Yanaga 2001 PMID: 11735257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Moreover, two other variants have been identified at this position (p.Arg162Pro, p.Arg162Gln) and have been classified by this laboratory as likely pathogenic, suggesting changes at this position are not tolerated. The available data on the p.Arg162Gln suggests that it may be a mild variant, with reduced penetrance. In summary, the p.Arg162Trp variant is likely pathogenic; however, this variant may have a milder role suggested by the incomplete penetrance seen in some family members and the individuals who were homozygous, similar to that observed for p.Arg162Gln. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PM5_Supporting, PP1, PS3_Supporting. -
Cardiomyopathy Pathogenic:2
- -
This missense variant replaces arginine with tryptophan at codon 162 of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant increases the Ca2+ sensitivity of cardiac muscle contraction (PMID: 10806205, 11735257). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 21799269, 21896538, 22429680, 24113344, 27532257, 30105547, 30847666, 32746448, 33495596, 33495597, 33673806). In one family, this variant was observed in homozygosity in two siblings affected with hypertrophic cardiomyopathy (PMID: 24113344). However, four heterozygous carriers from this family were not clinically affected. This variant has been identified in 10/249000 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at this codon, p.Arg162Pro and p.Arg162Gln, are considered to be disease-causing (ClinVar variant ID: 43390 and 43389), suggesting that arginine at this position is important for TNNI3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
not provided Pathogenic:2
Reported in the homozygous state in both a proband with HCM with features of a restrictive process and her brother with classic HCM; autosomal recessive inheritance was proposed as the four individuals heterozygous for the variant (both parents and two siblings) were clinically unaffected (Gray et al., 2013); Published functional studies demonstrate that this variant interferes with normal troponin function and is expected to impair cardiac muscle relaxation (Elliott et al., 2000; Takahashi-Yanaga et al., 2001); 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: 23299917, 24113344, 20298698, 20350521, 25351510, 15992656, 29551499, 29203298, 11735257, 23270746, 25637381, 10615387, 23840593, 25342278, 21967901, 22429680, 21839045, 21799269, 9241277, 27532257, 25649125, 15607392, 22876777, 15698845, 15070570, 25132132, 30105547, 32686758, 32830170, 28356264, 32746448, 33673806, 30847666, 31447099, 21896538, 10806205, 33487615) -
TNNI3: PM1, PM5, PS4:Moderate, PM2:Supporting, PS3:Supporting -
Cardiovascular phenotype Pathogenic:2
The p.R162W variant (also known as c.484C>T), located in coding exon 7 of the TNNI3 gene, results from a C to T substitution at nucleotide position 484. The arginine at codon 162 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in the heterozygous state in multiple individuals with hypertrophic cardiomyopathy (HCM) (Kimura A et al. Nat. Genet. 1997;16:379-82; Garcia-Pavia P et al. Eur. J. Heart Fail. 2011;13:1193-201; Santos S et al. BMC Med. Genet. 2012;13:17; Gómez J et al. Circ. J. 2014;78:2963-71 Lopes LR et al. Heart. 2015;101:294-301; Walsh R et al. Genet. Med. 2017;19:192-203). This alteration has also been detected in a pediatric cardiomyopathy cohort It has also been detected in the homozygous state in two siblings and a third, unrelated individual with HCM; however, their heterozygous relatives were unaffected (Das K J et al. Genet. Med. 2014;16:286-93; Gray B et al. Int. J. Cardiol. 2013;168:1530-1). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res. 2015;25:305-15). Functional studies suggest that this alteration impacts TNNI3 protein function (Elliott K et al. J. Biol. Chem. 2000;275:22069-74; Takahashi-Yanaga F et al. J. Mol. Cell. Cardiol. 2001;33:2095-107). Another variant at the same codon, p.R162Q (c.485G>A), has been described in association with HCM (Van Driest SL et al. Circulation. 2003;108(4):445-51). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is expected to be causative of autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is unclear. -
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. -
Hypertrophic cardiomyopathy 7;C1861861:Cardiomyopathy, familial restrictive, 1;C2678474:Dilated cardiomyopathy 2A;C2750091:Dilated cardiomyopathy 1FF Pathogenic:1
- -
Primary familial hypertrophic cardiomyopathy Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at