NM_000363.5(TNNI3):c.611G>A (p.Arg204His) AND Hypertrophic cardiomyopathy

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 8, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000469008.5

Allele description [Variation Report for NM_000363.5(TNNI3):c.611G>A (p.Arg204His)]

NM_000363.5(TNNI3):c.611G>A (p.Arg204His)

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.611G>A (p.Arg204His)
Other names:
p.R204H:CGC>CAC
HGVS:
  • NC_000019.10:g.55151856C>T
  • NG_007866.2:g.10877G>A
  • NG_011829.2:g.2383G>A
  • NM_000363.5:c.611G>AMANE SELECT
  • NP_000354.4:p.Arg204His
  • LRG_432t1:c.611G>A
  • LRG_432:g.10877G>A
  • LRG_679:g.2383G>A
  • NC_000019.9:g.55663224C>T
  • NM_000363.4:c.611G>A
  • P19429:p.Arg204His
Protein change:
R204H
Links:
UniProtKB: P19429#VAR_042746; dbSNP: rs727504275
NCBI 1000 Genomes Browser:
rs727504275
Molecular consequence:
  • NM_000363.5:c.611G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
4

Condition(s)

Name:
Hypertrophic cardiomyopathy
Identifiers:
MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; OMIM: PS192600; Human Phenotype Ontology: HP:0001639

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000203935Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(May 15, 2015)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000551899Invitaecriteria provided, single submitter
Pathogenic
(Oct 8, 2020)
germlineclinical testing

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

SCV000579527Center for Human Genetics,University of Leuvencriteria provided, single submitter
Likely pathogenic
(Feb 9, 2017)
de novoclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided32not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
Asian-Africande novoyes11not providednot providednoclinical testing
Caucasiande novoyes11not providednot providednoclinical testing

Citations

PubMed

Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling.

Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C.

J Med Genet. 2005 Oct;42(10):e59.

PubMed [citation]
PMID:
16199542
PMCID:
PMC1735926

Cardiac troponin mutations and restrictive cardiomyopathy.

Parvatiyar MS, Pinto JR, Dweck D, Potter JD.

J Biomed Biotechnol. 2010;2010:350706. doi: 10.1155/2010/350706. Epub 2010 Jun 8. Review.

PubMed [citation]
PMID:
20617149
PMCID:
PMC2896668
See all PubMed Citations (10)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000203935.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (6)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided3not provided2not provided

From Invitae, SCV000551899.4

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

Description

This sequence change replaces arginine with histidine at codon 204 of the TNNI3 protein (p.Arg204His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with restrictive cardiomyopathy (PMID: 29176140) and has been reported in several individuals affected with this disease or hypertrophic cardiomyopathy (PMID: 20569525, 18801787, 15698845, 27532257). ClinVar contains an entry for this variant (Variation ID: 177679). This variant has been reported to affect TNNI3 protein function (PMID: 27895589). For these reasons, this variant has been classified as Pathogenic.

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

From Center for Human Genetics,University of Leuven, SCV000579527.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Asian-African1not providednoclinical testingnot provided
2Caucasian1not providednoclinical testingnot provided

Description

Observed as de novo variant

Observed as de novo variant

Description

ACMG score likely pathogenic

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot provided1not provided1not provided
2de novoyesnot providednot providednot provided1not provided1not provided

Last Updated: Sep 29, 2021

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