NM_000363.5(TNNI3):c.574C>T (p.Arg192Cys) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 9, 2022
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:: RCV001066777.9

Allele description [Variation Report for NM_000363.5(TNNI3):c.574C>T (p.Arg192Cys)]

NM_000363.5(TNNI3):c.574C>T (p.Arg192Cys)

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.574C>T (p.Arg192Cys)

HGVS:

NC_000019.10:g.55151893G>A
NG_007866.2:g.10840C>T
NG_011829.2:g.2346C>T
NM_000363.5:c.574C>TMANE SELECT
NP_000354.4:p.Arg192Cys
LRG_432t1:c.574C>T
LRG_432:g.10840C>T
LRG_679:g.2346C>T
NC_000019.9:g.55663261G>A
NM_000363.4:c.574C>T

Protein change:

R192C

Links:

dbSNP: rs727503499

NCBI 1000 Genomes Browser:

rs727503499

Molecular consequence:

NM_000363.5:c.574C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001231797	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 9, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12531876, 25611685, 20800588, 21533915, 29907873, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001231797

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 9, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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

Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.

Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ.

J Clin Invest. 2003 Jan;111(2):209-16. Erratum in: J Clin Invest. 2003 Mar;111(6):925.

PubMed [citation]

PMID:: 12531876
PMCID:: PMC151864

Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.

Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL.

Genet Med. 2015 Nov;17(11):880-8. doi: 10.1038/gim.2014.205. Epub 2015 Jan 22. Erratum in: Genet Med. 2015 Apr;17(4):319.

PubMed [citation]

PMID:: 25611685

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001231797.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg192 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12531876, 25611685). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 165510). This missense change has been observed in individual(s) with clinical features of TNNI3-related conditions (PMID: 20800588, 21533915, 29907873; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 192 of the TNNI3 protein (p.Arg192Cys).

#	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: Apr 15, 2024

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