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NM_001276345.2(TNNT2):c.265A>T (p.Ile89Phe) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 8, 2023
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:
RCV000807862.7

Allele description [Variation Report for NM_001276345.2(TNNT2):c.265A>T (p.Ile89Phe)]

NM_001276345.2(TNNT2):c.265A>T (p.Ile89Phe)

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.265A>T (p.Ile89Phe)
HGVS:
  • NC_000001.11:g.201365639T>A
  • NG_007556.1:g.17039A>T
  • NM_000364.4:c.265A>T
  • NM_001001430.3:c.235A>T
  • NM_001001431.3:c.235A>T
  • NM_001001432.3:c.220A>T
  • NM_001276345.2:c.265A>TMANE SELECT
  • NM_001276346.2:c.262A>T
  • NM_001276347.2:c.235A>T
  • NP_000355.2:p.Ile89Phe
  • NP_001001430.1:p.Ile79Phe
  • NP_001001431.1:p.Ile79Phe
  • NP_001001432.1:p.Ile74Phe
  • NP_001263274.1:p.Ile89Phe
  • NP_001263275.1:p.Ile88Phe
  • NP_001263276.1:p.Ile79Phe
  • LRG_431t1:c.265A>T
  • LRG_431:g.17039A>T
  • LRG_431p1:p.Ile89Phe
  • NC_000001.10:g.201334767T>A
  • NM_001001430.2:c.235A>T
Protein change:
I74F
Links:
dbSNP: rs746297911
NCBI 1000 Genomes Browser:
rs746297911
Molecular consequence:
  • NM_000364.4:c.265A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001430.3:c.235A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001431.3:c.235A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001432.3:c.220A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276345.2:c.265A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276346.2:c.262A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276347.2:c.235A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hypertrophic cardiomyopathy 2
Synonyms:
Familial hypertrophic cardiomyopathy 2; TNNT2-Related Familial Hypertrophic Cardiomyopathy
Identifiers:
MONDO: MONDO:0007266; MedGen: C1861864; OMIM: 115195
Name:
Dilated cardiomyopathy 1D
Synonyms:
Left ventricular noncompaction 6
Identifiers:
MONDO: MONDO:0011095; MedGen: C1832243; Orphanet: 154; Orphanet: 54260; OMIM: 601494
Name:
Cardiomyopathy, familial restrictive, 3
Identifiers:
MONDO: MONDO:0012900; MedGen: C2676271; Orphanet: 75249; OMIM: 612422

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000947938Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(May 8, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.

Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE.

Cell. 1994 Jun 3;77(5):701-12.

PubMed [citation]
PMID:
8205619

Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology.

Menon SC, Michels VV, Pellikka PA, Ballew JD, Karst ML, Herron KJ, Nelson SM, Rodeheffer RJ, Olson TM.

Clin Genet. 2008 Nov;74(5):445-54. doi: 10.1111/j.1399-0004.2008.01062.x. Epub 2008 Jul 21.

PubMed [citation]
PMID:
18651846
PMCID:
PMC2575134
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000947938.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ile79 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8205619, 18651846, 26914223, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function. ClinVar contains an entry for this variant (Variation ID: 652329). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. This variant is present in population databases (rs746297911, gnomAD 0.007%). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 79 of the TNNT2 protein (p.Ile79Phe).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024