NM_001276345.2(TNNT2):c.835A>G (p.Asn279Asp) AND Cardiomyopathy

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 11, 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:: RCV000769738.8

Allele description [Variation Report for NM_001276345.2(TNNT2):c.835A>G (p.Asn279Asp)]

NM_001276345.2(TNNT2):c.835A>G (p.Asn279Asp)

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.835A>G (p.Asn279Asp)

HGVS:

NC_000001.11:g.201359639T>C
NG_007556.1:g.23039A>G
NM_000364.4:c.826A>G
NM_001001430.3:c.805A>G
NM_001001431.3:c.796A>G
NM_001001432.3:c.787A>G
NM_001276345.2:c.835A>GMANE SELECT
NM_001276346.2:c.706A>G
NM_001276347.2:c.805A>G
NP_000355.2:p.Asn276Asp
NP_001001430.1:p.Asn269Asp
NP_001001431.1:p.Asn266Asp
NP_001001432.1:p.Asn263Asp
NP_001263274.1:p.Asn279Asp
NP_001263275.1:p.Asn236Asp
NP_001263276.1:p.Asn269Asp
LRG_431t1:c.835A>G
LRG_431:g.23039A>G
LRG_431p1:p.Asn279Asp
NC_000001.10:g.201328767T>C
NM_001001430.1:c.805A>G
NM_001001430.2:c.805A>G
NM_001001430.3:c.805A>G

Protein change:

N236D

Links:

dbSNP: rs4523540

NCBI 1000 Genomes Browser:

rs4523540

Molecular consequence:

NM_000364.4:c.826A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001001430.3:c.805A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001001431.3:c.796A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001001432.3:c.787A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276345.2:c.835A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276346.2:c.706A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276347.2:c.805A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000901160	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 28, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001352680	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 1, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27532257, 33495597, 25741868
SCV004830818	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27532257, 33495597, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000901160

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 28, 2016)

germline

clinical testing

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

SCV001352680

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 1, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004830818

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

PubMed (3)
[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	3	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]

PMID:: 27532257
PMCID:: PMC5116235

Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.

Harper AR, Goel A, Grace C, Thomson KL, Petersen SE, Xu X, Waring A, Ormondroyd E, Kramer CM, Ho CY, Neubauer S; HCMR Investigators., Tadros R, Ware JS, Bezzina CR, Farrall M, Watkins H.

Nat Genet. 2021 Feb;53(2):135-142. doi: 10.1038/s41588-020-00764-0. Epub 2021 Jan 25.

PubMed [citation]

PMID:: 33495597
PMCID:: PMC8240954

See all PubMed Citations (3)

Details of each submission

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository, SCV000901160.1

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

From Color Diagnostics, LLC DBA Color Health, SCV001352680.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces asparagine with aspartic acid at codon 269 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 33495597). This variant has been identified in 1/225746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 All of Us Research Program, National Institutes of Health, SCV004830818.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (3)

Description

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: May 7, 2024

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