NM_000363.5(TNNI3):c.434G>A (p.Arg145Gln) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Dec 14, 2023
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:: RCV000200141.20

Allele description [Variation Report for NM_000363.5(TNNI3):c.434G>A (p.Arg145Gln)]

NM_000363.5(TNNI3):c.434G>A (p.Arg145Gln)

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.434G>A (p.Arg145Gln)

Other names:

p.R145Q:CGG>CAG

HGVS:

NC_000019.10:g.55154145C>T
NG_007866.2:g.8588G>A
NG_011829.2:g.94G>A
NM_000363.5:c.434G>AMANE SELECT
NP_000354.4:p.Arg145Gln
LRG_432t1:c.434G>A
LRG_432:g.8588G>A
LRG_679:g.94G>A
NC_000019.9:g.55665513C>T
NM_000363.4:c.434G>A
c.434G>A

Protein change:

R145Q

Links:

dbSNP: rs397516349

NCBI 1000 Genomes Browser:

rs397516349

Molecular consequence:

NM_000363.5:c.434G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059947	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Apr 5, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9241277, 11735257, 15607392, 3144325, 25741868
SCV000253695	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 14, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9241277, 15607392, 23283745, 24111713, 25132132, 21310275, 11735257, 20641121, 23610579, 28492532
SCV000579525	Center for Human Genetics, University of Leuven	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 9, 2017)	germline	clinical testing
SCV001245078	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 5, 2018)	germline	research	PubMed (10) [See all records that cite these PMIDs] 25132132, 11735257, 21533915, 28193612, 24111713, 23283745, 15607392, 9241277, 27532257, 25741868
SCV004819058	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jul 19, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 9241277, 11735257, 15607392, 21533915, 23283745, 24111713, 25132132, 27532257, 28193612, 29255176, 31737537, 32492895, 32686758, 33673806, 34137518, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing
Caucasian	germline	yes	5	2	not provided	not provided	yes	clinical testing

Citations

PubMed

Orthotic services: a need for change.

Platts RG.

BMJ. 1988 Nov 5;297(6657):1145-6. No abstract available.

PubMed [citation]

PMID:: 3144325
PMCID:: PMC1835028

Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy.

Jordan DM, Kiezun A, Baxter SM, Agarwala V, Green RC, Murray MF, Pugh T, Lebo MS, Rehm HL, Funke BH, Sunyaev SR.

Am J Hum Genet. 2011 Feb 11;88(2):183-92. doi: 10.1016/j.ajhg.2011.01.011.

PubMed [citation]

PMID:: 21310275
PMCID:: PMC3035712

See all PubMed Citations (21)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059947.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.Arg145Gln variant in TNNI3 has been reported in 10 individuals with HCM and 1 individual with RCM who also carried a second variant in TNNI3 (Berge 2014, Mogensen 2004, Kimura 1997, van den Wijngaard 2011, Wang 2014, Zou 2013, LMM data). This variant has also been reported in ClinVar (Variation ID 43384) as Pathogenic and Likely pathogenic, and in 2/17246 East Asian and 2/33578 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516349). This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In vitro functional studies provide some evidence that the p.Arg145Gln variant may impact protein function (Takahashi-Yanaga 2001). However, these types of assays may not accurately represent biological function. In addition, 2 other pathogenic variants have been reported at this amino acid position (p.Arg145Gly and p.Arg145Trp), suggesting that this residue has functional importance. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg145Gln variant is likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000253695.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 145 of the TNNI3 protein (p.Arg145Gln). This variant is present in population databases (rs397516349, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (HCM) (PMID: 9241277, 15607392, 23283745, 24111713, 25132132). ClinVar contains an entry for this variant (Variation ID: 43384). An algorithm developed specifically for the TNNI3 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). Experimental studies have shown that this missense change affects TNNI3 function (PMID: 11735257). This variant disrupts the p.Arg145 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11735257, 20641121, 23610579). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Human Genetics, University of Leuven, SCV000579525.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	5	not provided	yes	clinical testing	not provided

Description

ACMG score likely pathogenic

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		5	not provided	2	not provided

From Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV001245078.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (10)

Description

This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004819058.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (16)

Description

This missense variant replaces arginine with glutamine at codon 145 in the actin binding region of the TNNI3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant reduces the intrinsic inhibitory activity of the cardiac troponin I protein without changing the apparent affinity for actin and increases the Ca2+ sensitivity of cardiac muscle contraction (PMID: 11735257). This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 15607392, 23283745, 24111713, 25132132, 27532257, 28193612, 29255176, 32492895, 32686758, 34137518). In one family, it has been shown that this variant segregates with disease in three individuals affected with hypertrophic cardiomyopathy (PMID: 29255176). This variant has also been reported in individuals suspected to be affected with hypertrophic cardiomyopathy (PMID: 31737537, 33673806) and in an individual affected with restrictive cardiomyopathy (PMID: 21533915). This variant has been identified in 4/248984 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg145Trp and p.Arg145Gly, are considered to be disease-causing (ClinVar variation ID: 12426 and 12419), suggesting that arginine at this position is important for TNNI3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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