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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 18, 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:: RCV000167988.19

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:

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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mediator of RNA polymerase II transcription subunit 23 isoform X1 [Chiloscyllium...
mediator of RNA polymerase II transcription subunit 23 isoform X1 [Chiloscyllium plagiosum]
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059958	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 19, 2018)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 12707239, 15607392, 22301726, 23540544, 26169204, 20624503, 21310275, 27532257, 21239446, 16020591, 25524337, 24033266
SCV000218638	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12707239, 15607392, 20624503, 21239446, 23540544, 25524337, 27532257, 28492532
SCV000886795	Center for Human Genetics, University of Leuven	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059958

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Mar 19, 2018)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV000218638

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 18, 2024)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000886795

Center for Human Genetics, University of Leuven

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 31, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	5	4	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hypertrophic cardiomyopathy and planned in vitro fertilization. Genetic testing and clinical evaluation.

Zhu Hu J, Xiang Li J, Hong K, Xin Hu J, Brugada P, Shu Cheng X.

Herz. 2012 Jun;37(4):447-52. doi: 10.1007/s00059-011-3564-y.

PubMed [citation]

PMID:: 22301726

Identification of rare variants in TNNI3 with atrial fibrillation in a Chinese GeneID population.

Wang C, Wu M, Qian J, Li B, Tu X, Xu C, Li S, Chen S, Zhao Y, Huang Y, Shi L, Cheng X, Liao Y, Chen Q, Xia Y, Yao W, Wu G, Cheng M, Wang QK.

Mol Genet Genomics. 2016 Feb;291(1):79-92. doi: 10.1007/s00438-015-1090-y. Epub 2015 Jul 14.

PubMed [citation]

PMID:: 26169204
PMCID:: PMC4713376

See all PubMed Citations (14)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059958.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (12)

Description

The p.Arg186Gln variant in TNNI3 has been identified in at least 14 individuals with HCM, segregated with disease in 14 affected relatives from 4 families (Rich ard 2004, Mogensen 2004, Millat 2010, Fokstuen 2011, Zhu Hu 2012, Roberts 2013, Wang 2015, Walsh 2016, LMM data). It was absent from large population studies. I n summary, this variant meets our criteria to be classified as pathogenic for HC M in an autosomal dominant manner based upon case observations, segregation stud ies and absence from controls. ACMG/AMP Criteria applied: PS4; PP1_Strong; PM2; BP4.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		5	not provided	4	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000218638.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 186 of the TNNI3 protein (p.Arg186Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 20624503, 21239446, 23540544, 25524337, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43395). 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 disruptive. 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, SCV000886795.1

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

#	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	1	not provided

Last Updated: Sep 29, 2024

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