VCV000012424.24 - ClinVar

NM_000363.5(TNNI3):c.575G>A (p.Arg192His)

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.

(11)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000363.5(TNNI3):c.575G>A (p.Arg192His)

Variation ID: 12424 Accession: VCV000012424.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.42 19: 55151892 (GRCh38) [ NCBI UCSC ] 19: 55663260 (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	Apr 4, 2013	May 1, 2024	Feb 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000363.5:c.575G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000354.4:p.Arg192His	missense
NC_000019.10:g.55151892C>T
NC_000019.9:g.55663260C>T
NG_007866.2:g.10841G>A
NG_011829.2:g.2347G>A
LRG_432:g.10841G>A
LRG_432t1:c.575G>A
LRG_679:g.2347G>A
	P19429:p.Arg192His

... more HGVS ... less HGVS

Protein change

R192H

Other names

p.R192H:CGC>CAC

Canonical SPDI

NC_000019.10:55151891:C:T

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.

Links

ClinGen: CA021957 UniProtKB: P19429#VAR_016084 OMIM: 191044.0006 dbSNP: rs104894729 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	699	760

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.
Cardiomyopathy, familial restrictive, 1	Pathogenic (2)	criteria provided, single submitter	Feb 14, 2023	RCV000013237.24
Primary familial hypertrophic cardiomyopathy	Likely pathogenic (1)	no assertion criteria provided	Aug 22, 2014	RCV000157534.1
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 19, 2021	RCV000159242.8
Hypertrophic cardiomyopathy Restrictive cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	May 2, 2019	RCV000154212.6
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Dec 18, 2017	RCV000619328.3
Hypertrophic cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Sep 14, 2022	RCV000629012.9
Restrictive cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Jan 3, 2018	RCV000852483.1
Dilated cardiomyopathy 2A	Pathogenic (1)	criteria provided, single submitter	-	RCV003388566.2
SUDDEN INFANT DEATH SYNDROME	Pathogenic (1)	criteria provided, single submitter	Aug 8, 2022	RCV003147282.1

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.
Pathogenic (Oct 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502860.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (16) PubMed: 12531876‚ 25611685‚ 17463320‚ 18423659‚ 20161772‚ 29176140‚ 17027633‚ 18408133‚ 30279906‚ 29907873‚ 21310275‚ 16531415‚ 22675533‚ 19289050‚ 31912959‚ 27532257 Number of individuals with the variant: 2 Secondary finding: no
Pathogenic (Jun 22, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000209188.15 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (Lek et al., 2016); Functional studies demonstrate that R192H increases Ca2+ sensitivity compared to wild-type and increases the binding … (more) Not observed in large population cohorts (Lek et al., 2016); Functional studies demonstrate that R192H increases Ca2+ sensitivity compared to wild-type and increases the binding affinity of the thin filament (Gomes et al., 2005; Kobayashi et al., 2006; Liu et al., 2012); Du et al. (2006) demonstrated that transgenic mice harboring the mouse equivalent of R192H exhibit features characteristic of RCM; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic by other clinical laboratories, one of which found this variant to be de novo in two probands with either RCM or HCM (ClinVar Variant ID# 12424; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 20617149, 19449150, 31912959, 25611685, 29907873, 12531876, 15961398, 17463320, 18423659, 18408133, 19289050, 20161772, 21310275, 22783303, 21777381, 22675533, 23844019, 25649125, 24474965, 27532257, 31064352, 30279906, 29176140, 16531415, 17027633, 27535533, 26582918, 33673806) (less)
Pathogenic (Jan 03, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Restrictive cardiomyopathy Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995178.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
Pathogenic (May 02, 2019)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hypertrophic cardiomyopathy Restrictive cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000203865.6 First in ClinVar: Jan 31, 2015 Last updated: Jul 03, 2020	Publications: PubMed (11) PubMed: 19449150‚ 16531415‚ 17027633‚ 17463320‚ 18408133‚ 19289050‚ 20161772‚ 22675533‚ 23906401‚ 12531876‚ 15961398 Comment: The p.Arg192His variant in TNNI3 has been reported in 9 individuals with predominantly childhood onset RCM or HCM and occurred de novo in 4 of … (more) The p.Arg192His variant in TNNI3 has been reported in 9 individuals with predominantly childhood onset RCM or HCM and occurred de novo in 4 of these cases (Mogensen 2003, Gomes 2005, Rai 2009, Yang 2013, LMM data). This variant has not been identified in large population studies. In vitro studies have shown that the p.Arg192His variant impacts protein function (Gomes 2005, Kobayashi 2006, Davis 2007, Mathur 2009, Davis 2010, Liu 2012) and mouse models of this variant develop a restrictive cardiomyopathy phenotype (Du 2006, Du 2008). Finally, other likely disease-causing variants at this position (p.Arg192Cys, p.Arg192Leu) have been identified in individuals with RCM and HCM (Millat 2010, van den Wijngaard 2011, LMM data). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RCM and HCM. ACMG/AMP Criteria applied: PS3, PS4_Moderate, PM6_Strong, PM2, PM5. (less) Number of individuals with the variant: 9
Pathogenic (Aug 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SUDDEN INFANT DEATH SYNDROME Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835493.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 2A (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004100355.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Comment: The missense variant p.R192H in TNNI3 (NM_000363.5) causes the same amino acid change as a previously established pathogenic variant. The p.Arg192His variant in TNNI3 (NM_000363.5) … (more) The missense variant p.R192H in TNNI3 (NM_000363.5) causes the same amino acid change as a previously established pathogenic variant. The p.Arg192His variant in TNNI3 (NM_000363.5) has been reported in 9 individuals with predominantly childhood onset RCM or HCM and occurred de novo in 4 of these cases (Mogensen 2003, Gomes 2005, Rai 2009, Yang 2013). The p.R192H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The gene TNNI3 contains 38 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. 9 variants within 6 amino acid positions of the variant p.R192H have been shown to be pathogenic, while none have been shown to be benign. The p.R192H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 192 of TNNI3 is conserved in all mammalian species. The nucleotide c.575 in TNNI3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy, familial restrictive, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004176368.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: The missense c.575G>A(p.Arg192His) variant in TNNI3 gene has been reported previously in heterozygous state in multiple individuals affected with restrictive cardiomyopathy (Kohda M, et. al., … (more) The missense c.575G>A(p.Arg192His) variant in TNNI3 gene has been reported previously in heterozygous state in multiple individuals affected with restrictive cardiomyopathy (Kohda M, et. al., 2016; Rai TS, et. al., 2009; Mogensen J, et. al., 2003). Experimental studies have shown that this missense change affects TNNI3 function (Liu B, et. al., 2012; Du J, et. al., 2006). The p.Arg192His variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg192His in TNNI3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 192 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of the cardiovascular system (present)
Pathogenic (Sep 14, 2022)	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: SCV000749922.6 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Publications: PubMed (11) PubMed: 28492532‚ 16531415‚ 17027633‚ 17463320‚ 18408133‚ 18423659‚ 19289050‚ 20161772‚ 22675533‚ 12531876‚ 25611685 Comment: Experimental studies have shown that this missense change affects TNNI3 function (PMID: 16531415, 17027633, 17463320, 18408133, 18423659, 19289050, 20161772, 22675533). For these reasons, this variant … (more) Experimental studies have shown that this missense change affects TNNI3 function (PMID: 16531415, 17027633, 17463320, 18408133, 18423659, 19289050, 20161772, 22675533). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 12424). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and restrictive cardiomyopathy (PMID: 12531876, 25611685). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 192 of the TNNI3 protein (p.Arg192His). (less)
Pathogenic (Dec 18, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000740036.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Publications: PubMed (17) PubMed: 12531876‚ 15961398‚ 16531415‚ 17027633‚ 17463320‚ 18408133‚ 18423659‚ 19289050‚ 19449150‚ 20161772‚ 20800588‚ 21533915‚ 22675533‚ 24474965‚ 25440410‚ 25611685‚ 26741492 Comment: The p.R192H pathogenic mutation (also known as c.575G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at … (more) The p.R192H pathogenic mutation (also known as c.575G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 575. The arginine at codon 192 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals with restrictive cardiomyopathy and/or hypertrophic cardiomyopathy, often with a de novo or likely de novo origin (Mogensen J et al. J. Clin. Invest. 2003;111:209-16; Rai TS et al. Mol. Cell. Biochem. 2009;331:187-92; Alfares AA et al. Genet. Med. 2015;17:880-8; Chen Y et al. J Biomed Res. 2014;28:59-63; Thomas TO et al. Pediatr Transplant. 2015;19:E15-8; Kohda M et al. PLoS Genet. 2016;12:e1005679). Numerous in vitro functional assays, cardiomyocyte cell culture experiments, and mouse models have all indicated that p.R192H results in deficient function of the TNNI3 protein (e.g., Gomes AV et al. J. Biol. Chem. 2005;280:30909-15; Davis J et al. Circ. Res. 2007;100:1494-502; Du J et al. Am. J. Physiol. Heart Circ. Physiol. 2008;294:H2604-13; Liu B et al. PLoS ONE. 2012;7:e38259). In addition, two other alterations associated with RCM and/or HCM, p.R192C and p.R192L, have been described in the same codon (Millat G et al. Clin. Chim. Acta. 2010;411:1983-91; van den Wijngaard A et al. Neth Heart J. 2011;19:344-51; Alfares AA et al. Genet. Med. 2015;17:880-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Jan 01, 2003)	no assertion criteria provided Method: literature only	CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033484.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 12531876‚ 10098965 Comment on evidence: In an individual with restrictive cardiomyopathy (RCM1; 115210), Mogensen et al. (2003) identified a de novo 93G-A transition in exon 8 of the TNNI3 gene, … (more) In an individual with restrictive cardiomyopathy (RCM1; 115210), Mogensen et al. (2003) identified a de novo 93G-A transition in exon 8 of the TNNI3 gene, resulting in an arg192-to-his (R92H) substitution. (Mogensen et al. (2003) originally referred to the transition as 92C-A, which they later corrected in an erratum.) Arg192 is found in the conserved C-terminal region, which is required for normal inhibitory function of troponin (Perry, 1999). (less)
Likely pathogenic (Aug 22, 2014)	no assertion criteria provided Method: clinical testing	Primary familial hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000207280.1 First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015	Publications: PubMed (1) PubMed: 12531876 Number of individuals with the variant: 1
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Comment:

Not observed in large population cohorts (Lek et al., 2016); Functional studies demonstrate that R192H increases Ca2+ sensitivity compared to wild-type and increases the binding affinity of the thin filament (Gomes et al., 2005; Kobayashi et al., 2006; Liu et al., 2012); Du et al. (2006) demonstrated that transgenic mice harboring the mouse equivalent of R192H exhibit features characteristic of RCM; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic by other clinical laboratories, one of which found this variant to be de novo in two probands with either RCM or HCM (ClinVar Variant ID# 12424; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 20617149, 19449150, 31912959, 25611685, 29907873, 12531876, 15961398, 17463320, 18423659, 18408133, 19289050, 20161772, 21310275, 22783303, 21777381, 22675533, 23844019, 25649125, 24474965, 27532257, 31064352, 30279906, 29176140, 16531415, 17027633, 27535533, 26582918, 33673806)

Comment:

The p.Arg192His variant in TNNI3 has been reported in 9 individuals with predominantly childhood onset RCM or HCM and occurred de novo in 4 of these cases (Mogensen 2003, Gomes 2005, Rai 2009, Yang 2013, LMM data). This variant has not been identified in large population studies. In vitro studies have shown that the p.Arg192His variant impacts protein function (Gomes 2005, Kobayashi 2006, Davis 2007, Mathur 2009, Davis 2010, Liu 2012) and mouse models of this variant develop a restrictive cardiomyopathy phenotype (Du 2006, Du 2008). Finally, other likely disease-causing variants at this position (p.Arg192Cys, p.Arg192Leu) have been identified in individuals with RCM and HCM (Millat 2010, van den Wijngaard 2011, LMM data). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RCM and HCM. ACMG/AMP Criteria applied: PS3, PS4_Moderate, PM6_Strong, PM2, PM5.

Comment:

The missense variant p.R192H in TNNI3 (NM_000363.5) causes the same amino acid change as a previously established pathogenic variant. The p.Arg192His variant in TNNI3 (NM_000363.5) has been reported in 9 individuals with predominantly childhood onset RCM or HCM and occurred de novo in 4 of these cases (Mogensen 2003, Gomes 2005, Rai 2009, Yang 2013). The p.R192H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The gene TNNI3 contains 38 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. 9 variants within 6 amino acid positions of the variant p.R192H have been shown to be pathogenic, while none have been shown to be benign. The p.R192H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 192 of TNNI3 is conserved in all mammalian species. The nucleotide c.575 in TNNI3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Comment:

The missense c.575G>A(p.Arg192His) variant in TNNI3 gene has been reported previously in heterozygous state in multiple individuals affected with restrictive cardiomyopathy (Kohda M, et. al., 2016; Rai TS, et. al., 2009; Mogensen J, et. al., 2003). Experimental studies have shown that this missense change affects TNNI3 function (Liu B, et. al., 2012; Du J, et. al., 2006). The p.Arg192His variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg192His in TNNI3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 192 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

Comment:

Experimental studies have shown that this missense change affects TNNI3 function (PMID: 16531415, 17027633, 17463320, 18408133, 18423659, 19289050, 20161772, 22675533). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 12424). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and restrictive cardiomyopathy (PMID: 12531876, 25611685). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 192 of the TNNI3 protein (p.Arg192His).

Comment:

The p.R192H pathogenic mutation (also known as c.575G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 575. The arginine at codon 192 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals with restrictive cardiomyopathy and/or hypertrophic cardiomyopathy, often with a de novo or likely de novo origin (Mogensen J et al. J. Clin. Invest. 2003;111:209-16; Rai TS et al. Mol. Cell. Biochem. 2009;331:187-92; Alfares AA et al. Genet. Med. 2015;17:880-8; Chen Y et al. J Biomed Res. 2014;28:59-63; Thomas TO et al. Pediatr Transplant. 2015;19:E15-8; Kohda M et al. PLoS Genet. 2016;12:e1005679). Numerous in vitro functional assays, cardiomyocyte cell culture experiments, and mouse models have all indicated that p.R192H results in deficient function of the TNNI3 protein (e.g., Gomes AV et al. J. Biol. Chem. 2005;280:30909-15; Davis J et al. Circ. Res. 2007;100:1494-502; Du J et al. Am. J. Physiol. Heart Circ. Physiol. 2008;294:H2604-13; Liu B et al. PLoS ONE. 2012;7:e38259). In addition, two other alterations associated with RCM and/or HCM, p.R192C and p.R192L, have been described in the same codon (Millat G et al. Clin. Chim. Acta. 2010;411:1983-91; van den Wijngaard A et al. Neth Heart J. 2011;19:344-51; Alfares AA et al. Genet. Med. 2015;17:880-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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
Investigation of de novo variation in pediatric cardiomyopathy.	Parrott A	American journal of medical genetics. Part C, Seminars in medical genetics	2020	PMID: 31912959
The TNNI3 Arg192His mutation in a 13-year-old girl with left ventricular noncompaction.	Fujino M	Journal of cardiology cases	2018	PMID: 30279906
Genetic background of Japanese patients with pediatric hypertrophic and restrictive cardiomyopathy.	Hayashi T	Journal of human genetics	2018	PMID: 29907873
Role of Whole-exome Sequencing in Phenotype Classification and Clinical Treatment of Pediatric Restrictive Cardiomyopathy.	Ding WH	Chinese medical journal	2017	PMID: 29176140
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
A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies.	Kohda M	PLoS genetics	2016	PMID: 26741492
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.	Alfares AA	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25611685
The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman's disease.	Thomas TO	Pediatric transplantation	2015	PMID: 25440410
Pediatric restrictive cardiomyopathy due to a heterozygous mutation of the TNNI3 gene.	Chen Y	Journal of biomedical research	2014	PMID: 24474965
[Clinical characteristics and genetic analysis of three pediatric patients with idiopathic restrictive cardiomyopathy].	Yang SW	Zhonghua xin xue guan bing za zhi	2013	PMID: 23906401
Disease-related cardiac troponins alter thin filament Ca2+ association and dissociation rates.	Liu B	PloS one	2012	PMID: 22675533
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
Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy.	Jordan DM	American journal of human genetics	2011	PMID: 21310275
Development of a high resolution melting method for the detection of genetic variations in hypertrophic cardiomyopathy.	Millat G	Clinica chimica acta; international journal of clinical chemistry	2010	PMID: 20800588
Combinatorial effects of double cardiomyopathy mutant alleles in rodent myocytes: a predictive cellular model of myofilament dysregulation in disease.	Davis J	PloS one	2010	PMID: 20161772
Genetic and clinical profile of Indian patients of idiopathic restrictive cardiomyopathy with and without hypertrophy.	Rai TS	Molecular and cellular biochemistry	2009	PMID: 19449150
Some cardiomyopathy-causing troponin I mutations stabilize a functional intermediate actin state.	Mathur MC	Biophysical journal	2009	PMID: 19289050
Allele and species dependent contractile defects by restrictive and hypertrophic cardiomyopathy-linked troponin I mutants.	Davis J	Journal of molecular and cellular cardiology	2008	PMID: 18423659
Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI.	Du J	American journal of physiology. Heart and circulatory physiology	2008	PMID: 18408133
Thin filament disinhibition by restrictive cardiomyopathy mutant R193H troponin I induces Ca2+-independent mechanical tone and acute myocyte remodeling.	Davis J	Circulation research	2007	PMID: 17463320
A point mutation (R192H) in the C-terminus of human cardiac troponin I causes diastolic dysfunction in transgenic mice.	Du J	Archives of biochemistry and biophysics	2006	PMID: 17027633
Increased Ca2+ affinity of cardiac thin filaments reconstituted with cardiomyopathy-related mutant cardiac troponin I.	Kobayashi T	The Journal of biological chemistry	2006	PMID: 16531415
Mutations in human cardiac troponin I that are associated with restrictive cardiomyopathy affect basal ATPase activity and the calcium sensitivity of force development.	Gomes AV	The Journal of biological chemistry	2005	PMID: 15961398
Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.	Mogensen J	The Journal of clinical investigation	2003	PMID: 12531876
Troponin I: inhibitor or facilitator.	Perry SV	Molecular and cellular biochemistry	1999	PMID: 10098965
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Text-mined citations for rs104894729 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000363.5(TNNI3):c.575G>A (p.Arg192His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894729 ...