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NM_000363.5(TNNI3):c.485G>A (p.Arg162Gln) AND Hypertrophic cardiomyopathy

Germline classification:
Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:
Jan 16, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000197981.22

Allele description [Variation Report for NM_000363.5(TNNI3):c.485G>A (p.Arg162Gln)]

NM_000363.5(TNNI3):c.485G>A (p.Arg162Gln)

Gene:
TNNI3:troponin I3, cardiac type [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19q13.42
Genomic location:
Preferred name:
NM_000363.5(TNNI3):c.485G>A (p.Arg162Gln)
Other names:
p.R162Q:CGG>CAG
HGVS:
  • NC_000019.10:g.55154094C>T
  • NG_007866.2:g.8639G>A
  • NG_011829.2:g.145G>A
  • NM_000363.5:c.485G>AMANE SELECT
  • NP_000354.4:p.Arg162Gln
  • LRG_432t1:c.485G>A
  • LRG_432:g.8639G>A
  • LRG_679:g.145G>A
  • NC_000019.9:g.55665462C>T
  • NM_000363.4:c.485G>A
  • P19429:p.Arg162Gln
  • c.485G>A
  • p.R162Q
Protein change:
R162Q
Links:
UniProtKB: P19429#VAR_042745; dbSNP: rs397516354
NCBI 1000 Genomes Browser:
rs397516354
Molecular consequence:
  • NM_000363.5:c.485G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
5

Condition(s)

Name:
Hypertrophic cardiomyopathy
Synonyms:
HYPERTROPHIC MYOCARDIOPATHY
Identifiers:
MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000059952Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Nov 18, 2021) 		germlineclinical testing

PubMed (23)
[See all records that cite these PMIDs]

SCV000253837Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 16, 2024) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000996359Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Mar 28, 2017) 		germlineresearch

PubMed (14)
[See all records that cite these PMIDs]

SCV004819051All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Jan 8, 2024) 		germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
not providedgermlineunknown5not providednot provided108544not providedclinical testing

Citations

PubMed

Homozygous mutation in the cardiac troponin I gene: clinical heterogeneity in hypertrophic cardiomyopathy.

Gray B, Yeates L, Medi C, Ingles J, Semsarian C.

Int J Cardiol. 2013 Sep 30;168(2):1530-1. doi: 10.1016/j.ijcard.2012.12.008. Epub 2012 Dec 25. No abstract available.

PubMed [citation]
PMID:
23270746

Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy.

Elliott K, Watkins H, Redwood CS.

J Biol Chem. 2000 Jul 21;275(29):22069-74.

PubMed [citation]
PMID:
10806205
See all PubMed Citations (28)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059952.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (23)

Description

The p.Arg162Gln variant in TNNI3 has been reported in >20 individuals with HCM, one of whom was homozygous and 3 of whom also carried other pathogenic variants in HCM-associated genes. This variant also segregated with disease in >10 affected relatives from multiple families (Van Driest 2003 PMID:12860912, Mogensen 2004 PMID:15607392, Doolan 2005 PMID:15698845, Cheng 2005 PMID:15992656, Ingles 2005 PMID:16199542, Bos 2006 PMID:16352453, Gruner 2011 PMID:21511876, Rani 2012 PMID:22876777, Kapplinger 2014 PMID:24510615, Mouton 2015 PMID:25940119, Cecconi 2016 PMID 27600940, Burns 2017 PMID 28790153, Walsh 2017 PMID 27532257, Lorenzini 2020 PMID 32731933, LMM data). However, the p.Arg162Gln variant was also present in several unaffected relatives, many of whom were older than 50, suggesting reduced penetrance or a milder role (Mogensen 2004 PMID: 15607392, LMM data). This variant did not segregate with disease in 1 affected relative, although this discrepancy may be explained by the presence of more than 1 pathogenic variant in this family or an environmental origin of disease. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43389) and was also identified in 0.005% (6/113172) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies using a mammalian two-hybrid system suggests that this variant may impact protein function by affecting the interaction with other binding partners (troponin T and troponin C; Doolan 2005 PMID:15698845). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Additionally, two different variants at this position (p.Arg162Pro and p.Arg162Trp) were identified in multiple individuals with HCM (Kimura 1997 PMID:9241277, Richard 2005 PMID:12707239, Doolan 2005 PMID:15698845, Ingles 2005 PMID:16199542, Gray 2013 PMID:23270746, LMM data), suggesting that a change of this amino acid residue is not tolerated. In summary, the p.Arg162Gln variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM; however, this variant may have a milder role suggested by the incomplete penetrance seen in some family members and the individuals who were homozygous or double heterozygous. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Strong, PS3_Supporting, BP4.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000253837.12

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 162 of the TNNI3 protein (p.Arg162Gln). This variant is present in population databases (rs397516354, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12860912, 15607392, 15698845, 15992656, 16352453, 22876777). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43389). 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 tolerated. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 15698845). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV000996359.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (14)

Description

TNNI3 Arg162Gln has been identified in multiple HCM probands (Walsh R, et al., 2017; Cecconi M, et al., 2016; Mouton JM, et al., 2015; Coppini R, et la., 2014; Kapplinger JD, et al., 2014; Rani DS, et al., 2012; Bos JM, et al., 2006; Mogensen J, et al., 2004; Van Driest SL, et al., 2003) and has been found to segregate with disease in 2 HCM families (Rani DS, et al., 2012; Mogensen J, et al., 2004). The variant is present at a low frequency in the Exome Aggregation Consortium dataset (MAF=0.00003; http://exac.broadinstitute.org/). We have identified this variant in 3 HCM probands (Burns et al., 2017), one of their families have been previously described (Ingles J, et al., 2005; Doolan A, et al., 2005). Computational tools CADD, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect, however SIFT predicts this variant to be "tolerated". A mammalian two-hybrid system has shown that this missense change decreases troponin T and troponin C interaction (Doolan A, et al., 2005), whereas crystal structure modelling suggests that the Arg162Gln affects troponin C stability (Ramachandran G, et al., 2013). In summary, the TNNI3 Arg162Gln is a rare variant which has been described in multiple HCM probands around the world and has been found to segregate strongly in at least 2 families, therefore we classify this variant as "pathogenic".

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004819051.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided5not providednot providedclinical testing PubMed (11)

Description

This missense variant replaces arginine with glutamine at codon 162 of the TNNI3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant disrupts interactions with troponin C and T (PMID: 15698845). However, clinical relevance of this observation is not known. This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12860912, 15607392, 15698845, 15992656, 16352453, 25940119, 31877599, 33029862, 3349559, Yang et al 2018). This variant has been shown to segregate with hypertrophic cardiomyopathy in a family study (PMID: 22876777). This variant has also been reported in the homozygous state in an individual affected with severe, early-onset hypertrophic cardiomyopathy (PMID: 31877599). The proband's four relatives were asymptomatic heterozygous carriers. This variant has been identified in 10/249030 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg162Pro and p.Arg162Trp, are known to cause disease (Clinvar variation ID: 43390, 161396), indicating that arginine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided5not providednot providednot provided

Last Updated: Nov 24, 2024