NM_001276345.2(TNNT2):c.287A>C (p.Asp96Ala) AND multiple conditions

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 5, 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:: RCV000556483.9

Allele description [Variation Report for NM_001276345.2(TNNT2):c.287A>C (p.Asp96Ala)]

NM_001276345.2(TNNT2):c.287A>C (p.Asp96Ala)

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.287A>C (p.Asp96Ala)

HGVS:

NC_000001.11:g.201365617T>G
NG_007556.1:g.17061A>C
NM_000364.4:c.287A>C
NM_001001430.3:c.257A>C
NM_001001431.3:c.257A>C
NM_001001432.3:c.242A>C
NM_001276345.2:c.287A>CMANE SELECT
NM_001276346.2:c.284A>C
NM_001276347.2:c.257A>C
NP_000355.2:p.Asp96Ala
NP_001001430.1:p.Asp86Ala
NP_001001431.1:p.Asp86Ala
NP_001001432.1:p.Asp81Ala
NP_001263274.1:p.Asp96Ala
NP_001263275.1:p.Asp95Ala
NP_001263276.1:p.Asp86Ala
LRG_431t1:c.287A>C
LRG_431:g.17061A>C
LRG_431p1:p.Asp96Ala
NC_000001.10:g.201334745T>G
NM_001001430.1:c.257A>C
NM_001001430.2:c.257A>C
NM_001276345.2:c.287A>C
c.257A>C

Protein change:

D81A

Links:

dbSNP: rs397516455

NCBI 1000 Genomes Browser:

rs397516455

Molecular consequence:

NM_000364.4:c.287A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001001430.3:c.257A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001001431.3:c.257A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001001432.3:c.242A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276345.2:c.287A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276346.2:c.284A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276347.2:c.257A>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000646894	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12860912, 20159828, 25031304, 26914223, 27532257, 28973951, 28492532
SCV002791893	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 16, 2021)	unknown	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

SCV000646894

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 5, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002791893

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 16, 2021)

unknown

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	unknown	unknown	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

Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy.

Van Driest SL, Ellsworth EG, Ommen SR, Tajik AJ, Gersh BJ, Ackerman MJ.

Circulation. 2003 Jul 29;108(4):445-51. Epub 2003 Jul 14.

PubMed [citation]

PMID:: 12860912

Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies.

Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM.

Circulation. 2010 Mar 2;121(8):997-1004. doi: 10.1161/CIRCULATIONAHA.109.904557. Epub 2010 Feb 16.

PubMed [citation]

PMID:: 20159828
PMCID:: PMC2857348

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000646894.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 86 of the TNNT2 protein (p.Asp86Ala). This variant is present in population databases (rs397516455, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12860912, 20159828, 25031304, 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 43626). 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 with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNNT2 function (PMID: 28973951). This variant disrupts the p.Asp86 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been observed in individuals with TNNT2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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 Fulgent Genetics, Fulgent Genetics, SCV002791893.1

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

Last Updated: Sep 29, 2024

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