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NM_000363.5(TNNI3):c.592C>G (p.Leu198Val)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(3);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
4 (Most recent: Jan 7, 2021)
Last evaluated:
Jul 26, 2020
Accession:
VCV000177694.7
Variation ID:
177694
Description:
single nucleotide variant
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NM_000363.5(TNNI3):c.592C>G (p.Leu198Val)

Allele ID
176068
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19q13.42
Genomic location
19: 55151875 (GRCh38) GRCh38 UCSC
19: 55663243 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_432:g.10858C>G
LRG_432t1:c.592C>G
NC_000019.10:g.55151875G>C
... more HGVS
Protein change
L198V
Other names
p.L198V:CTG>GTG
Canonical SPDI
NC_000019.10:55151874:G:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA022019
dbSNP: rs727504285
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Aug 3, 2016 RCV000154294.4
Likely pathogenic 1 criteria provided, single submitter Dec 20, 2018 RCV000518842.2
Likely pathogenic 1 criteria provided, single submitter Jul 26, 2020 RCV000628864.5
Likely pathogenic 1 criteria provided, single submitter Jul 12, 2017 RCV000623545.2
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
TNNI3 Little evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
438 493

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely pathogenic
(Dec 20, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000209193.8
Submitted: (Jan 29, 2019)
Evidence details
Comment:
The L198V likely pathogenic variant in the TNNI3 gene has been identified in multiple unrelated individuals with HCM referred for genetic testing at GeneDx and … (more)
Uncertain significance
(Aug 03, 2016)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000203953.4
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (7)
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu198Val variant in TNNI3 has been reported in 6 individuals with HCM and segregated wit h … (more)
Likely pathogenic
(Jul 12, 2017)
criteria provided, single submitter
Method: clinical testing
None
Allele origin: germline
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute
Accession: SCV000740430.1
Submitted: (Aug 02, 2017)
Evidence details
Likely pathogenic
(Jul 26, 2020)
criteria provided, single submitter
Method: clinical testing
Hypertrophic cardiomyopathy
Allele origin: germline
Invitae
Accession: SCV000749772.5
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (6)
Comment:
This sequence change replaces leucine with valine at codon 198 of the TNNI3 protein (p.Leu198Val). The leucine residue is highly conserved and there is a … (more)

Functional evidence

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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.

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
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
Merits and pitfalls of genetic testing in a hypertrophic cardiomyopathy clinic. Arad M The Israel Medical Association journal : IMAJ 2014 PMID: 25558701
Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. Coppini R Journal of the American College of Cardiology 2014 PMID: 25524337
Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy. Otsuka H Circulation journal : official journal of the Japanese Circulation Society 2012 PMID: 22112859
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
Mutations in Troponin that cause HCM, DCM AND RCM: what can we learn about thin filament function? Willott RH Journal of molecular and cellular cardiology 2010 PMID: 19914256
Genetic and biochemical heterogeneity of cardiac troponins: clinical and laboratory implications. Lippi G Clinical chemistry and laboratory medicine 2009 PMID: 19754353
Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. Baudenbacher F The Journal of clinical investigation 2008 PMID: 19033660
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

Text-mined citations for rs727504285...

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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, 2021