VCV000043639.9 - ClinVar

NM_001276345.2(TNNT2):c.430C>G (p.Arg144Gly)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001276345.2(TNNT2):c.430C>G (p.Arg144Gly)

Variation ID: 43639 Accession: VCV000043639.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q32.1 1: 201364357 (GRCh38) [ NCBI UCSC ] 1: 201333485 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 31, 2015	Feb 28, 2024	Apr 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001276345.2:c.430C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001263274.1:p.Arg144Gly	missense
NM_000364.4:c.430C>G	NP_000355.2:p.Arg144Gly	missense
NM_001001430.3:c.400C>G	NP_001001430.1:p.Arg134Gly	missense
NM_001001431.3:c.400C>G	NP_001001431.1:p.Arg134Gly	missense
NM_001001432.3:c.385C>G	NP_001001432.1:p.Arg129Gly	missense
NM_001276346.2:c.310C>G	NP_001263275.1:p.Arg104Gly	missense
NM_001276347.2:c.400C>G	NP_001263276.1:p.Arg134Gly	missense
NC_000001.11:g.201364357G>C
NC_000001.10:g.201333485G>C
NG_007556.1:g.18321C>G
LRG_431:g.18321C>G
LRG_431t1:c.430C>G	LRG_431p1:p.Arg144Gly

... more HGVS ... less HGVS

Protein change

R134G, R144G, R129G, R104G

Other names

Canonical SPDI

NC_000001.11:201364356:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA004479 dbSNP: rs45525839 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TNNT2		No evidence available	No evidence available	GRCh38 GRCh37	959	978

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Primary dilated cardiomyopathy	Likely pathogenic (1)	criteria provided, single submitter	Feb 21, 2014	RCV000036587.5
Dilated cardiomyopathy 1D	Likely pathogenic (1)	criteria provided, single submitter	Apr 11, 2023	RCV003450702.1
Cardiomyopathy, familial restrictive, 3	Likely pathogenic (1)	criteria provided, single submitter	Apr 11, 2023	RCV003450703.1
Cardiomyopathy, familial restrictive, 3 Dilated cardiomyopathy 1D Hypertrophic cardiomyopathy 2	Pathogenic (1)	criteria provided, single submitter	Apr 17, 2022	RCV002513390.3
Hypertrophic cardiomyopathy 2	Likely pathogenic (1)	criteria provided, single submitter	Apr 11, 2023	RCV003450701.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 21, 2014)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Primary dilated cardiomyopathy (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000060242.6 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Publications: PubMed (2) PubMed: 19412328‚ 20031601 Comment: The Arg134Gly variant in TNNT2 has been reported in 1 individual with DCM, was a bsent from 506 control chromosomes, and segregated with disease in … (more) The Arg134Gly variant in TNNT2 has been reported in 1 individual with DCM, was a bsent from 506 control chromosomes, and segregated with disease in 4 affected re latives from 1 family (Hershberger 2008, Hershberger 2009). Data from large popu lation studies is insufficient to assess the frequency of this variant. This var iant has also been identified by our laboratory in 1 Caucasian individual with D CM (this family) and segregated with disease in 3 affected relatives, but was no t detected in 1 other affected relative (more distantly related). Arginine (Arg) at position 134 is conserved in evolution and the change to glycine (Gly) was p redicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant is likely pathogenic, though a dditional studies are required to fully establish its clinical significance. (less) Number of individuals with the variant: 4
Likely pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1D Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004181398.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Likely pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy, familial restrictive, 3 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004181399.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Likely pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 2 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004181400.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Apr 17, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cardiomyopathy, familial restrictive, 3 Hypertrophic cardiomyopathy 2 Dilated cardiomyopathy 1D Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003523947.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 20031601‚ 33025817‚ 34161147 Comment: This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 134 of the TNNT2 protein (p.Arg134Gly). … (more) This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 134 of the TNNT2 protein (p.Arg134Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20031601, 33025817). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43639). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 20031601, 34161147). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

The Arg134Gly variant in TNNT2 has been reported in 1 individual with DCM, was a bsent from 506 control chromosomes, and segregated with disease in 4 affected re latives from 1 family (Hershberger 2008, Hershberger 2009). Data from large popu lation studies is insufficient to assess the frequency of this variant. This var iant has also been identified by our laboratory in 1 Caucasian individual with D CM (this family) and segregated with disease in 3 affected relatives, but was no t detected in 1 other affected relative (more distantly related). Arginine (Arg) at position 134 is conserved in evolution and the change to glycine (Gly) was p redicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant is likely pathogenic, though a dditional studies are required to fully establish its clinical significance.

Comment:

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 134 of the TNNT2 protein (p.Arg134Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20031601, 33025817). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43639). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 20031601, 34161147). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A troponin T variant linked with pediatric dilated cardiomyopathy reduces the coupling of thin filament activation to myosin and calcium binding.	Barrick SK	Molecular biology of the cell	2021	PMID: 34161147
Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human TNNT2 Variants.	Pettinato AM	Circulation	2020	PMID: 33025817
Clinical and functional characterization of TNNT2 mutations identified in patients with dilated cardiomyopathy.	Hershberger RE	Circulation. Cardiovascular genetics	2009	PMID: 20031601
Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.	Hershberger RE	Clinical and translational science	2008	PMID: 19412328

Text-mined citations for rs45525839 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001276345.2(TNNT2):c.430C>G (p.Arg144Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs45525839 ...