NM_000363.5(TNNI3):c.586G>A (p.Asp196Asn) AND Cardiomyopathy

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 11, 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:: RCV000777480.7

Allele description [Variation Report for NM_000363.5(TNNI3):c.586G>A (p.Asp196Asn)]

NM_000363.5(TNNI3):c.586G>A (p.Asp196Asn)

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.586G>A (p.Asp196Asn)

Other names:

p.D196N:GAT>AAT

HGVS:

NC_000019.10:g.55151881C>T
NG_007866.2:g.10852G>A
NG_011829.2:g.2358G>A
NM_000363.5:c.586G>AMANE SELECT
NP_000354.4:p.Asp196Asn
LRG_432t1:c.586G>A
LRG_432:g.10852G>A
LRG_679:g.2358G>A
NC_000019.9:g.55663249C>T
NM_000363.4:c.586G>A
P19429:p.Asp196Asn
c.586G>A

Protein change:

D196N; ASP196ASN

Links:

UniProtKB: P19429#VAR_016085; OMIM: 191044.0004; dbSNP: rs104894727

NCBI 1000 Genomes Browser:

rs104894727

Molecular consequence:

NM_000363.5:c.586G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000913342	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 11, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12707239, 15607392, 24111713, 25524337, 26914223, 27532257, 34363016, 25741868
SCV004239772	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 1, 2022)	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

SCV000913342

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 11, 2023)

germline

clinical testing

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

SCV004239772

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 1, 2022)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.

Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M; EUROGENE Heart Failure Project..

Circulation. 2003 May 6;107(17):2227-32. Epub 2003 Apr 21. Erratum in: Circulation. 2004 Jun 29;109(25):3258.

PubMed [citation]

PMID:: 12707239

Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy.

Mogensen J, Murphy RT, Kubo T, Bahl A, Moon JC, Klausen IC, Elliott PM, McKenna WJ.

J Am Coll Cardiol. 2004 Dec 21;44(12):2315-25.

PubMed [citation]

PMID:: 15607392

See all PubMed Citations (8)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000913342.4

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

Description

This missense variant replaces aspartic acid with asparagine at codon 196 in the C-terminal mobile domain 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 24111713, 25524337, 26914223, 27532257), and in an individual with a family history of hypertrophic cardiomyopathy (PMID: 34363016). In two unrelated families, this variant was identified in 4 of 7 family members affected with hypertrophic cardiomyopathy (PMID: 15607392). This variant has been identified in 2/280974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV004239772.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 12, 2024

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