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NM_000363.5(TNNI3):c.557G>A (p.Arg186Gln) AND not provided

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Aug 5, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000223924.5

Allele description [Variation Report for NM_000363.5(TNNI3):c.557G>A (p.Arg186Gln)]

NM_000363.5(TNNI3):c.557G>A (p.Arg186Gln)

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.557G>A (p.Arg186Gln)
HGVS:
  • NC_000019.10:g.55151910C>T
  • NG_007866.2:g.10823G>A
  • NG_011829.2:g.2329G>A
  • NM_000363.5:c.557G>AMANE SELECT
  • NP_000354.4:p.Arg186Gln
  • LRG_432t1:c.557G>A
  • LRG_432:g.10823G>A
  • LRG_679:g.2329G>A
  • NC_000019.9:g.55663278C>T
  • NM_000363.4:c.557G>A
  • P19429:p.Arg186Gln
  • c.557G>A
Protein change:
R186Q
Links:
UniProtKB: P19429#VAR_019876; dbSNP: rs397516357
NCBI 1000 Genomes Browser:
rs397516357
Molecular consequence:
  • NM_000363.5:c.557G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
4

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000209185GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Pathogenic
(Aug 5, 2021) 		germlineclinical testing

Citation Link,

SCV000280512Stanford Center for Inherited Cardiovascular Disease, Stanford University
no assertion criteria provided
Pathogenic
(Mar 1, 2011) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided4not providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000209185.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33297573, 33567718, 33673806, 31513939, 28567093, 26169204, 21239446, 12707239, 25524337, 16020591, 23540544, 27681577, 28166811, 26199943, 26183555, 23782526, 20624503, 15524171, 19754353, 27532257, 21310275, 22301726, 15607392)

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

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280512.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testingnot provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. The patient had HCM genetic testing with the GeneDx laboratory. The test included sequencing of 18 genes associated with HCM: MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC, MYL3, MYL2, LAMP2, PRKAG2, GLA, CAV3, MTTG, MTTI, MTTK, MTTQ, TTR, and TNNC1. Results reported on Nov 23rd 2010 showed that a variant associated with disease was identified: p.Arg186Gln (c.557G>A) in the TNNI3 gene. This variant has been reported in multiple cases of HCM. Richard et al (2003) found the p.Arg186Gln variant in one individual with HCM. No segregation data was reported. Mogensen et al (2004) observed the variant in two unrelated families with HCM. Segregation data was not reported separately for each family, however of 11 total genotype positive individuals in both families, 5 had HCM. No other variants have been reported at codon 186, however a variant has been reported with HCM at a nearby codon (p. Lys183Glu (Mogensen et al 2004)). Arginine is highly conserved across species and isoforms at position 186. This variant substitutes a polar, positively charged amino acid (Arg) with a polar, neutral amino acid (Gln). Richard et al (2003) did not identify the variant in 100 presumably healthy controls of unspecified ethnicity and Mogenson et al (2004) did not observe it in 75 presumably healthy individuals, for a total of 175 controls. Based on these data it is very likely that this variant causes cardiomyopathy.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided4not providednot providednot provided

Last Updated: Feb 28, 2024