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

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 6, 2024
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:: RCV000618563.3

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:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000740173	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Feb 6, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12860912, 20159828, 24793961, 25524337, 26914223, 27532257, 28973951, 29121657 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000740173

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Feb 6, 2024)

germline

clinical testing

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

Citation Link

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

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 Ambry Genetics, SCV000740173.5

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

Description

The p.D86A variant (also known as c.257A>C), located in coding exon 7 of the TNNT2 gene, results from an A to C substitution at nucleotide position 257. The aspartic acid at codon 86 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with hypertrophic cardiomyopathy and has been reported to segregate with disease in several small families (Van Driest SL et al. Circulation, 2003 Jul;108:445-51; Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-2600; Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Ambry internal data; external communication). Internal structural analysis indicates that this variant may impact the protein-protein interaction with tropomyosin (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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

Last Updated: Sep 29, 2024

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