NM_001276345.2(TNNT2):c.692T>C (p.Ile231Thr) AND Dilated cardiomyopathy 1D

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: May 21, 2020
Review status:: criteria provided, conflicting classifications

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:: RCV001196994.5

Allele description [Variation Report for NM_001276345.2(TNNT2):c.692T>C (p.Ile231Thr)]

NM_001276345.2(TNNT2):c.692T>C (p.Ile231Thr)

Gene:

TNNT2:troponin T2, cardiac type [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q32.1

Genomic location:

Preferred name:

NM_001276345.2(TNNT2):c.692T>C (p.Ile231Thr)

Other names:

p.I221T:ATT>ACT

HGVS:

NC_000001.11:g.201361940A>G
NG_007556.1:g.20738T>C
NM_000364.4:c.683T>C
NM_001001430.3:c.662T>C
NM_001001431.3:c.653T>C
NM_001001432.3:c.644T>C
NM_001276345.2:c.692T>CMANE SELECT
NM_001276346.2:c.563T>C
NM_001276347.2:c.662T>C
NP_000355.2:p.Ile228Thr
NP_001001430.1:p.Ile221Thr
NP_001001431.1:p.Ile218Thr
NP_001001432.1:p.Ile215Thr
NP_001263274.1:p.Ile231Thr
NP_001263275.1:p.Ile188Thr
NP_001263276.1:p.Ile221Thr
LRG_431t1:c.692T>C
LRG_431:g.20738T>C
LRG_431p1:p.Ile231Thr
NC_000001.10:g.201331068A>G
NM_000364.3:c.683T>C
NM_001001430.1:c.662T>C
NM_001001430.2:c.662T>C
NM_001276345.1:c.692T>C

Protein change:

I188T

Links:

dbSNP: rs45520032

NCBI 1000 Genomes Browser:

rs45520032

Molecular consequence:

NM_000364.4:c.683T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001001430.3:c.662T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001001431.3:c.653T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001001432.3:c.644T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276345.2:c.692T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276346.2:c.563T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276347.2:c.662T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Dilated cardiomyopathy 1D
Synonyms:: Left ventricular noncompaction 6
Identifiers:: MONDO: MONDO:0011095; MedGen: C1832243; Orphanet: 154; Orphanet: 54260; OMIM: 601494

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001367629	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002768616	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (May 21, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24093860, 26507537, 28255936, 30763825, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001367629

Centre for Mendelian Genomics, University Medical Centre Ljubljana

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 31, 2018)

unknown

clinical testing

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

SCV002768616

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(May 21, 2020)

germline

clinical testing

PubMed (5)
[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	unknown	yes	not provided	not provided	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

Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy.

Marsiglia JD, Credidio FL, de Oliveira TG, Reis RF, Antunes Mde O, de Araujo AQ, Pedrosa RP, Barbosa-Ferreira JM, Mady C, Krieger JE, Arteaga-Fernandez E, Pereira Ada C.

Am Heart J. 2013 Oct;166(4):775-82. doi: 10.1016/j.ahj.2013.07.029. Epub 2013 Sep 18.

PubMed [citation]

PMID:: 24093860

Clinical and Prognostic Profiles of Cardiomyopathies Caused by Mutations in the Troponin T Gene.

Ripoll-Vera T, Gámez JM, Govea N, Gómez Y, Núñez J, Socías L, Escandell Á, Rosell J.

Rev Esp Cardiol (Engl Ed). 2016 Feb;69(2):149-58. doi: 10.1016/j.rec.2015.06.025. Epub 2015 Oct 24.

PubMed [citation]

PMID:: 26507537

See all PubMed Citations (5)

Details of each submission

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001367629.2

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

Description

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3,BP6.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768616.1

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

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely benign. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine (exon 13). (N) 0251 - Variant is heterozygous. (N) 0308 - Population frequency for this variant is out of keeping with known incidence of DCM (45 heterozygotes, 0 homozygotes). (B) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif. (Troponin coiled-coiled; PDB) (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. (N) p.Ile228Val reported VUS in two individuals (ClinVar). 0808 - Previous reports of pathogenicity are conflicting. (N) Reported as VUS in four individuals and likely benign in one individual (ClinVar), one patient with ARVC and DCM (Te Rijdt, W. et al (2019)), two HCM patients (Marsiglia, J. et al. (2013), Ripoll-Vera, T. et al. (2016)), one sudden death patient (Campuzano, O. et al. (2017)). 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

#	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 3, 2025

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Relating variation to medicine