VCV003254590.1 - ClinVar

NM_001276345.2(TNNT2):c.284T>A (p.Val95Glu)

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.

(1)

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.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001276345.2(TNNT2):c.284T>A (p.Val95Glu)

Variation ID: 3254590 Accession: VCV003254590.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q32.1 1: 201365620 (GRCh38) [ NCBI UCSC ] 1: 201334748 (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	Jul 23, 2024	Jul 23, 2024	Mar 31, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001276345.2:c.284T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001263274.1:p.Val95Glu	missense
NM_000364.4:c.284T>A	NP_000355.2:p.Val95Glu	missense
NM_001001430.3:c.254T>A	NP_001001430.1:p.Val85Glu	missense
NM_001001431.3:c.254T>A	NP_001001431.1:p.Val85Glu	missense
NM_001001432.3:c.239T>A	NP_001001432.1:p.Val80Glu	missense
NM_001276346.2:c.281T>A	NP_001263275.1:p.Val94Glu	missense
NM_001276347.2:c.254T>A	NP_001263276.1:p.Val85Glu	missense
NM_001406723.1:c.284T>A	NP_001393652.1:p.Val95Glu	missense
NM_001406724.1:c.254T>A	NP_001393653.1:p.Val85Glu	missense
NM_001406725.1:c.251T>A	NP_001393654.1:p.Val84Glu	missense
NM_001406726.1:c.254T>A	NP_001393655.1:p.Val85Glu	missense
NM_001406727.1:c.254T>A	NP_001393656.1:p.Val85Glu	missense
NM_001406728.1:c.239T>A	NP_001393657.1:p.Val80Glu	missense
NC_000001.11:g.201365620A>T
NC_000001.10:g.201334748A>T
NG_007556.1:g.17058T>A
LRG_431:g.17058T>A
LRG_431t1:c.284T>A	LRG_431p1:p.Val95Glu

... more HGVS ... less HGVS

Protein change

V80E, V84E, V85E, V94E, V95E

Other names

Canonical SPDI

NC_000001.11:201365619:A:T

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

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.
Dilated cardiomyopathy 1D	Uncertain significance (1)	criteria provided, single submitter	Mar 31, 2022	RCV004594773.1

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.
Uncertain significance (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1D (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086270.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (7) PubMed: 14972426‚ 18612386‚ 19659763‚ 26507537‚ 30847666‚ 32098556‚ 33025817 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Functional studies have suggested loss-of-function, gain-of-function and dominant-negative mechanisms based on calcium sensitivity, contractibility and mouse models (PMID: 18612386, 32098556, 33025817). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity, e.g., the variant, p.(Arg92Gln), has been reported to cause both DCM and HCM, even within the same family (PMID: 26507537). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change, p.(Val95Leu), has been reported as pathogenic, and observed in a single individual with hypertrophic cardiomyopathy (HCM) (LOVD, PMID: 14972426). Another alternative change, p.(Val95Met), has been reported as a VUS and observed in two unrelated individuals with HCM (LOVD, PMID: 19659763, PMID: 30847666). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Functional studies have suggested loss-of-function, gain-of-function and dominant-negative mechanisms based on calcium sensitivity, contractibility and mouse models (PMID: 18612386, 32098556, 33025817). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity, e.g., the variant, p.(Arg92Gln), has been reported to cause both DCM and HCM, even within the same family (PMID: 26507537). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change, p.(Val95Leu), has been reported as pathogenic, and observed in a single individual with hypertrophic cardiomyopathy (HCM) (LOVD, PMID: 14972426). Another alternative change, p.(Val95Met), has been reported as a VUS and observed in two unrelated individuals with HCM (LOVD, PMID: 19659763, PMID: 30847666). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human TNNT2 Variants.	Pettinato AM	Circulation	2020	PMID: 33025817
Variant R94C in TNNT2-Encoded Troponin T Predisposes to Pediatric Restrictive Cardiomyopathy and Sudden Death Through Impaired Thin Filament Relaxation Resulting in Myocardial Diastolic Dysfunction.	Ezekian JE	Journal of the American Heart Association	2020	PMID: 32098556
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666
Clinical and Prognostic Profiles of Cardiomyopathies Caused by Mutations in the Troponin T Gene.	Ripoll-Vera T	Revista espanola de cardiologia (English ed.)	2016	PMID: 26507537
A child cohort study from southern Italy enlarges the genetic spectrum of hypertrophic cardiomyopathy.	Frisso G	Clinical genetics	2009	PMID: 19659763
The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy.	Ahmad F	PloS one	2008	PMID: 18612386
Diagnostic value of abnormal Q waves for identification of preclinical carriers of hypertrophic cardiomyopathy based on a molecular genetic diagnosis.	Konno T	European heart journal	2004	PMID: 14972426

Text-mined citations for this variant ...

Record last updated Sep 17, 2024

ClinVar Genomic variation as it relates to human health

NM_001276345.2(TNNT2):c.284T>A (p.Val95Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...