NM_001276345.2(TNNT2):c.473G>A (p.Arg158Gln) AND multiple conditions

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 31, 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:: RCV001361925.9

Allele description [Variation Report for NM_001276345.2(TNNT2):c.473G>A (p.Arg158Gln)]

NM_001276345.2(TNNT2):c.473G>A (p.Arg158Gln)

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.473G>A (p.Arg158Gln)

Other names:

p.R148Q:CGG>CAG

HGVS:

NC_000001.11:g.201364314C>T
NG_007556.1:g.18364G>A
NM_000364.4:c.473G>A
NM_001001430.3:c.443G>A
NM_001001431.3:c.443G>A
NM_001001432.3:c.428G>A
NM_001276345.2:c.473G>AMANE SELECT
NM_001276346.2:c.353G>A
NM_001276347.2:c.443G>A
NP_000355.2:p.Arg158Gln
NP_001001430.1:p.Arg148Gln
NP_001001431.1:p.Arg148Gln
NP_001001432.1:p.Arg143Gln
NP_001263274.1:p.Arg158Gln
NP_001263275.1:p.Arg118Gln
NP_001263276.1:p.Arg148Gln
LRG_431t1:c.473G>A
LRG_431:g.18364G>A
LRG_431p1:p.Arg158Gln
NC_000001.10:g.201333442C>T
NM_001001430.1:c.443G>A
NM_001276345.2:c.473G>A

Protein change:

R118Q

Links:

dbSNP: rs730881102

NCBI 1000 Genomes Browser:

rs730881102

Molecular consequence:

NM_000364.4:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001001430.3:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001001431.3:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001001432.3:c.428G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276345.2:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276346.2:c.353G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276347.2:c.443G>A - 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

Recent activity

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hypothetical protein PNEG_01471 [Pneumocystis murina B123]
hypothetical protein PNEG_01471 [Pneumocystis murina B123]
gi|470318545|gnl|WGS:AFWA|PNEG_0147 EMR10198.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001557918	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 31, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30565988, 28492532
SCV002814562	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 17, 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

SCV001557918

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 31, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002814562

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 17, 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

Functional Annotation of TNNT2 Variants of Uncertain Significance With Genome-Edited Cardiomyocytes.

Lv W, Qiao L, Petrenko N, Li W, Owens AT, McDermott-Roe C, Musunuru K.

Circulation. 2018 Dec 11;138(24):2852-2854. doi: 10.1161/CIRCULATIONAHA.118.035028. No abstract available.

PubMed [citation]

PMID:: 30565988
PMCID:: PMC6309910

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001557918.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 148 of the TNNT2 protein (p.Arg148Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. This variant is also known as R158Q. ClinVar contains an entry for this variant (Variation ID: 181618). 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 have shown that this missense change affects TNNT2 function (PMID: 30565988). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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 Fulgent Genetics, Fulgent Genetics, SCV002814562.1

#	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: May 1, 2024

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