NM_001276345.2(TNNT2):c.887G>A (p.Arg296His) AND Cardiomyopathy

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Oct 30, 2023
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:: RCV001187862.9

Allele description [Variation Report for NM_001276345.2(TNNT2):c.887G>A (p.Arg296His)]

NM_001276345.2(TNNT2):c.887G>A (p.Arg296His)

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.887G>A (p.Arg296His)

HGVS:

NC_000001.11:g.201359220C>T
NG_007556.1:g.23458G>A
NM_000364.4:c.878G>A
NM_001001430.3:c.857G>A
NM_001001431.3:c.848G>A
NM_001001432.3:c.839G>A
NM_001276345.2:c.887G>AMANE SELECT
NM_001276346.2:c.758G>A
NM_001276347.2:c.857G>A
NP_000355.2:p.Arg293His
NP_001001430.1:p.Arg286His
NP_001001431.1:p.Arg283His
NP_001001432.1:p.Arg280His
NP_001263274.1:p.Arg296His
NP_001263275.1:p.Arg253His
NP_001263276.1:p.Arg286His
LRG_431t1:c.887G>A
LRG_431:g.23458G>A
LRG_431p1:p.Arg296His
NC_000001.10:g.201328348C>T
NM_000364.2:c.878G>A
NM_001001430.1:c.857G>A
NM_001001430.2:c.857G>A
NM_001276345.2:c.887G>A
NM_001276346.1:c.758G>A
c.857G>A

Protein change:

R253H

Links:

dbSNP: rs141121678

NCBI 1000 Genomes Browser:

rs141121678

Molecular consequence:

NM_000364.4:c.878G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001001430.3:c.857G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001001431.3:c.848G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001001432.3:c.839G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276345.2:c.887G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276346.2:c.758G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276347.2:c.857G>A - 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
SCV001354764	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 26, 2022)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 12860912, 19035361, 23711808, 24111713, 25086479, 25351510, 26507537, 27082122, 27532257, 28356264, 28771489, 32815737, 25741868
SCV002042864	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 26, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004817898	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 30, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 12860912, 19035361, 23711808, 24111713, 25086479, 25351510, 26507537, 27082122, 27532257, 28356264, 28771489, 32815737, 33495596, 33495597, 37107598, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001354764

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 26, 2022)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV002042864

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 26, 2023)

germline

clinical testing

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

SCV004817898

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 30, 2023)

germline

clinical testing

PubMed (16)
[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	6	not provided	not provided	108544	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

Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives.

Andersen PS, Havndrup O, Hougs L, Sørensen KM, Jensen M, Larsen LA, Hedley P, Thomsen AR, Moolman-Smook J, Christiansen M, Bundgaard H.

Hum Mutat. 2009 Mar;30(3):363-70. doi: 10.1002/humu.20862.

PubMed [citation]

PMID:: 19035361

See all PubMed Citations (16)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001354764.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This missense variant replaces arginine with histidine at codon 286 of the TNNT2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies using induced pluripotent stem cells provide some evidence that this variant may impact TNNT2 function (PMID: 32815737). This variant has been reported in multiple individuals and families affected with hypertrophic cardiomyopathy (PMID: 12860912, 19035361, 23711808, 24111713, 25086479, 25351510, 26507537, 27082122, 27532257, 28356264, 28771489, 32815737). Compound heterozygous individuals showed a more severe phenotype than heterozygous individuals (PMID: 25086479). Family studies are inconclusive as to whether this variant segregates with hypertrophic cardiomyopathy or not (PMID: 19035361, 25086479, 26507537). This variant has been identified in healthy control cohorts, and is estimated to have a low penetrance (PMID: 32815737). This variant has been identified in 19/273936 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant with unknown functional impact that has been reported in multiple individuals affected with hypertrophic cardiomyopathy. However, this variant also occurs at an appreciable frequency in the general population and it is inconclusive whether this variant segregates with disease in affected families. Additional studies are necessary 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 CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV002042864.3

#	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 All of Us Research Program, National Institutes of Health, SCV004817898.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (16)

Description

This missense variant replaces arginine with histidine at codon 286 of the TNNT2 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies using induced pluripotent stem cells provide some evidence that this variant may impact TNNT2 function (PMID: 32815737). This variant has been reported in multiple individuals and families affected with hypertrophic cardiomyopathy (PMID: 12860912, 19035361, 23711808, 24111713, 25086479, 25351510, 26507537, 27082122, 27532257, 28356264, 28771489, 32815737, 33495596, 33495597, 37107598). Some of these individuals also carried pathogenic variants in other genes associated with hypertrophic cardiomyopathy (PMID: 25086479 , 37107598). Compound heterozygous individuals showed a more severe phenotype than heterozygous individuals (PMID: 25086479). Family studies are inconclusive as to whether this variant segregates with hypertrophic cardiomyopathy or not (PMID: 19035361, 25086479, 26507537). This variant has been identified in healthy control cohorts, and is estimated to have a low penetrance (PMID: 32815737). This variant has been identified in 19/273936 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant with unknown functional impact that has been reported in multiple individuals affected with hypertrophic cardiomyopathy. However, this variant also occurs at an appreciable frequency in the general population and it is inconclusive whether this variant segregates with disease in affected families. Additional studies are necessary 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	108544	not provided	not provided		6	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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