VCV000161396.56 - ClinVar

NM_000363.5(TNNI3):c.484C>T (p.Arg162Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(19)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(4); Likely pathogenic(10); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000363.5(TNNI3):c.484C>T (p.Arg162Trp)

Variation ID: 161396 Accession: VCV000161396.56

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.42 19: 55154095 (GRCh38) [ NCBI UCSC ] 19: 55665463 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 7, 2014	Nov 24, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000363.5:c.484C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000354.4:p.Arg162Trp	missense
NC_000019.10:g.55154095G>A
NC_000019.9:g.55665463G>A
NG_007866.2:g.8638C>T
NG_011829.2:g.144C>T
LRG_432:g.8638C>T
LRG_432t1:c.484C>T
LRG_679:g.144C>T

... more HGVS ... less HGVS

Protein change

R162W

Other names

p.R162W:CGG>TGG

Canonical SPDI

NC_000019.10:55154094:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA021738 dbSNP: rs368861241 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TNNI3		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	700	761

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Primary familial hypertrophic cardiomyopathy	Uncertain significance (1)	no assertion criteria provided	Jun 1, 2014	RCV000148896.11
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000159228.14
Hypertrophic cardiomyopathy 7	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Apr 4, 2024	RCV000709765.10
Cardiomyopathy	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 9, 2023	RCV001170615.11
Hypertrophic cardiomyopathy	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000475238.22
Cardiovascular phenotype	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 20, 2023	RCV000722122.7
Cardiomyopathy, familial restrictive, 1 Dilated cardiomyopathy 1FF Dilated cardiomyopathy 2A Hypertrophic cardiomyopathy 7	Pathogenic (1)	criteria provided, single submitter	Aug 14, 2021	RCV002498682.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jan 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001333204.3 First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000551900.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (18) PubMed: 9241277‚ 21799269‚ 21896538‚ 22429680‚ 25132132‚ 27532257‚ 28356264‚ 30847666‚ 32746448‚ 33673806‚ 10806205‚ 11735257‚ 12860912‚ 15607392‚ 15698845‚ 15992656‚ 16352453‚ 22876777 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 30, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 7 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000840074.1 First in ClinVar: Oct 14, 2018 Last updated: Oct 14, 2018	Comment: 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 … (more) 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. (less)
Likely pathogenic (Oct 08, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000203864.6 First in ClinVar: Jan 31, 2015 Last updated: May 29, 2021	Publications: PubMed (12) PubMed: 9241277‚ 10806205‚ 11735257‚ 15070570‚ 21896538‚ 24113344‚ 23270746‚ 21799269‚ 22429680‚ 28356264‚ 27532257‚ 25637381 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 11
Likely pathogenic (Jul 27, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696595.3 First in ClinVar: Mar 08, 2017 Last updated: Dec 11, 2022	Publications: PubMed (12) PubMed: 10806205‚ 9241277‚ 11735257‚ 22429680‚ 21839045‚ 25342278‚ 24113344‚ 21896538‚ 23270746‚ 20350521‚ 25132132‚ 21967901 Comment: 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 … (more) 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. (less)
Pathogenic (Aug 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy, familial restrictive, 1 Dilated cardiomyopathy 2A Dilated cardiomyopathy 1FF Hypertrophic cardiomyopathy 7 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002805269.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Apr 25, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000209174.15 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Likely pathogenic (May 09, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001351203.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (14) PubMed: 9241277‚ 10806205‚ 11735257‚ 21799269‚ 21896538‚ 22429680‚ 24113344‚ 27532257‚ 30105547‚ 30847666‚ 32746448‚ 33495596‚ 33495597‚ 33673806 Comment: 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 … (more) 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. (less)
Uncertain significance (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 7 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004809817.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Likely Pathogenic (Jan 06, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004819053.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (14) PubMed: 9241277‚ 10806205‚ 11735257‚ 21799269‚ 21896538‚ 22429680‚ 24113344‚ 27532257‚ 30105547‚ 30847666‚ 32746448‚ 33495596‚ 33495597‚ 33673806 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 4
Likely pathogenic (Oct 20, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002634099.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (28) PubMed: 10806205‚ 11735257‚ 20350521‚ 21799269‚ 21839045‚ 21896538‚ 22429680‚ 23270746‚ 23299917‚ 24113344‚ 25342278‚ 25351510‚ 25637381‚ 27532257‚ 28138913‚ 28356264‚ 28408708‚ 29203298‚ 29551499‚ 30105547‚ 30297972‚ 32686758‚ 32746448‚ 32830170‚ 33487615‚ 33673806‚ 35288587‚ 9241277 Comment: 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 … (more) 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 alteration 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. (less)
Likely pathogenic (Jun 17, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	hypertrophic cardiomyopathy Affected status: unknown Allele origin: unknown	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV005045738.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Comment: 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 … (more) 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. (less)
Likely pathogenic (Nov 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 7 Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Region Ostergotland Accession: SCV005045205.2 First in ClinVar: May 26, 2024 Last updated: Sep 16, 2024 Comment: Heterozygous	Comment: PS4, PP3, PM5
Uncertain significance (Oct 19, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 7 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398064.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (9) PubMed: 10806205‚ 15070570‚ 15607392‚ 21533915‚ 23270746‚ 27532257‚ 28420666‚ 32686758‚ 32830170 Comment: 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 … (more) 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 (less)
Likely pathogenic (Dec 03, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypertrophic cardiomyopathy 7 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001164414.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Publications: PubMed (6) PubMed: 24113344‚ 23270746‚ 22429680‚ 21799269‚ 11735257‚ 10806205 Comment: 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) … (more) 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). (less)
Likely pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV005092183.3 First in ClinVar: Aug 04, 2024 Last updated: Oct 20, 2024	Comment: TNNI3: PM1, PM5, PS4:Moderate, PM2:Supporting, PS3:Supporting Number of individuals with the variant: 1
Uncertain significance (Jun 01, 2014)	no assertion criteria provided Method: research	Cardiomyopathy, hypertrophic (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190642.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Likely pathogenic (Mar 23, 2020)	no assertion criteria provided Method: research	Hypertrophic cardiomyopathy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute Accession: SCV001430827.1 First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020	Publications: PubMed (12) PubMed: 20350521‚ 9241277‚ 10806205‚ 11735257‚ 21896538‚ 21839045‚ 21967901‚ 22429680‚ 23270746‚ 25132132‚ 27532257‚ 28356264 Comment: 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 … (more) 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. (less)
Pathogenic (Apr 01, 2023)	no assertion criteria provided Method: clinical testing	Hypertrophic cardiomyopathy 7 Affected status: yes Allele origin: germline	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) Accession: SCV003927945.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023
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Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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 alteration 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.

Comment:

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.

Comment:

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

Comment:

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).

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy.	Lesurf R	NPJ genomic medicine	2022	PMID: 35288587
Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients.	Hathaway J	BMC cardiovascular disorders	2021	PMID: 33673806
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.	Harper AR	Nature genetics	2021	PMID: 33495597
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.	Tadros R	Nature genetics	2021	PMID: 33495596
A Validation Study of the Mayo Clinic Phenotype-Based Genetic Test Prediction Score for Japanese Patients With Hypertrophic Cardiomyopathy.	Moriki T	Circulation journal : official journal of the Japanese Circulation Society	2021	PMID: 33487615
Genetic variant burden and adverse outcomes in pediatric cardiomyopathy.	Burstein DS	Pediatric research	2021	PMID: 32746448
Lifelong Clinical Impact of the Presence of Sarcomere Gene Mutation in Japanese Patients With Hypertrophic Cardiomyopathy.	Nakashima Y	Circulation journal : official journal of the Japanese Circulation Society	2020	PMID: 32830170
Secondary findings in inherited heart conditions: a genotype-first feasibility study to assess phenotype, behavioural and psychosocial outcomes.	Ormondroyd E	European journal of human genetics : EJHG	2020	PMID: 32686758
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666
Genetic basis of hypertrophic cardiomyopathy in children.	Rupp S	Clinical research in cardiology : official journal of the German Cardiac Society	2019	PMID: 30105547
Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).	Ho CY	Circulation	2018	PMID: 30297972
A novel splicing variant in FLNC gene responsible for a highly penetrant familial dilated cardiomyopathy in an extended Iranian family.	Nozari A	Gene	2018	PMID: 29551499
The Genetic and Molecular Bases for Hypertrophic Cardiomyopathy: The Role for Calcium Sensitization.	Ren X	Journal of cardiothoracic and vascular anesthesia	2018	PMID: 29203298
Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy: Revisiting the Gene-Dose Effect.	Fourey D	Circulation. Cardiovascular genetics	2017	PMID: 28420666
Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications.	Ingles J	Circulation. Cardiovascular genetics	2017	PMID: 28408708
Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.	Gómez J	Circulation. Cardiovascular genetics	2017	PMID: 28356264
Usefulness of Genetic Testing in Hypertrophic Cardiomyopathy: an Analysis Using Real-World Data.	Alejandra Restrepo-Cordoba M	Journal of cardiovascular translational research	2017	PMID: 28138913
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510
Mutation analysis of the main hypertrophic cardiomyopathy genes using multiplex amplification and semiconductor next-generation sequencing.	Gómez J	Circulation journal : official journal of the Japanese Circulation Society	2014	PMID: 25342278
Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy.	Wang J	European journal of heart failure	2014	PMID: 25132132
Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment.	Das K J	Genetics in medicine : official journal of the American College of Medical Genetics	2014	PMID: 24113344
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.	Andreasen C	European journal of human genetics : EJHG	2013	PMID: 23299917
Homozygous mutation in the cardiac troponin I gene: clinical heterogeneity in hypertrophic cardiomyopathy.	Gray B	International journal of cardiology	2013	PMID: 23270746
High prevalence of Arginine to Glutamine substitution at 98, 141 and 162 positions in Troponin I (TNNI3) associated with hypertrophic cardiomyopathy among Indians.	Rani DS	BMC medical genetics	2012	PMID: 22876777
High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort.	Santos S	BMC medical genetics	2012	PMID: 22429680
Myocardial contractile and metabolic properties of familial hypertrophic cardiomyopathy caused by cardiac troponin I gene mutations: a simulation study.	Wu B	Experimental physiology	2012	PMID: 21967901
Double or compound sarcomere mutations in hypertrophic cardiomyopathy: a potential link to sudden death in the absence of conventional risk factors.	Maron BJ	Heart rhythm	2012	PMID: 21839045
Genetic basis of end-stage hypertrophic cardiomyopathy.	Garcia-Pavia P	European journal of heart failure	2011	PMID: 21896538
Genetic screening and double mutation in Japanese patients with hypertrophic cardiomyopathy.	Kubo T	Circulation journal : official journal of the Japanese Circulation Society	2011	PMID: 21799269
Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy.	van den Wijngaard A	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2011	PMID: 21533915
A novel cardiac myosin-binding protein C S297X mutation in hypertrophic cardiomyopathy.	Hirota T	Journal of cardiology	2010	PMID: 20350521
Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin.	Bos JM	Molecular genetics and metabolism	2006	PMID: 16352453
Frequency of cardiac troponin I mutations in families with hypertrophic cardiomyopathy in China.	Cheng TO	Journal of the American College of Cardiology	2005	PMID: 15992656
Cardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy: clinical, genetic and functional consequences.	Doolan A	Journal of molecular and cellular cardiology	2005	PMID: 15698845
Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy.	Mogensen J	Journal of the American College of Cardiology	2004	PMID: 15607392
Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy.	Murphy RT	Lancet (London, England)	2004	PMID: 15070570
Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy.	Van Driest SL	Circulation	2003	PMID: 12860912
Functional consequences of the mutations in human cardiac troponin I gene found in familial hypertrophic cardiomyopathy.	Takahashi-Yanaga F	Journal of molecular and cellular cardiology	2001	PMID: 11735257
Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy.	Elliott K	The Journal of biological chemistry	2000	PMID: 10806205
Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.	Kimura A	Nature genetics	1997	PMID: 9241277
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Text-mined citations for rs368861241 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000363.5(TNNI3):c.484C>T (p.Arg162Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs368861241 ...