VCV000044336.42 - ClinVar

NM_001308093.3(GATA4):c.825C>T (p.Cys275=)

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.

(16)

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.

Conflicting classifications of pathogenicity
Uncertain significance(5); Benign(2); Likely benign(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001308093.3(GATA4):c.825C>T (p.Cys275=)

Variation ID: 44336 Accession: VCV000044336.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p23.1 8: 11750149 (GRCh38) [ NCBI UCSC ] 8: 11607658 (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	May 29, 2016	Oct 20, 2024	Apr 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001308093.3:c.825C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001295022.1:p.Cys275=	synonymous
NM_001308094.2:c.204C>T	NP_001295023.1:p.Cys68=	synonymous
NM_001374273.1:c.204C>T	NP_001361202.1:p.Cys68=	synonymous
NM_001374274.1:c.165+1064C>T		intron variant
NM_002052.5:c.822C>T	NP_002043.2:p.Cys274=	synonymous
NC_000008.11:g.11750149C>T
NC_000008.10:g.11607658C>T
NG_008177.2:g.78231C>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000008.11:11750148:C: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.

0.00180 (T)

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

1000 Genomes Project 30x 0.00172

1000 Genomes Project 0.00180

The Genome Aggregation Database (gnomAD), exomes 0.00221

Exome Aggregation Consortium (ExAC) 0.00224

Trans-Omics for Precision Medicine (TOPMed) 0.00270

The Genome Aggregation Database (gnomAD) 0.00275

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00308

Links

ClinGen: CA133997 dbSNP: rs55980825 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.
GATA4		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	808	931

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.
not specified	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Nov 4, 2016	RCV000037324.12
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Sep 15, 2016	RCV000249584.5
Atrioventricular septal defect 4	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Feb 1, 2024	RCV000228063.16
Ventricular septal defect 1	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2017	RCV000578024.2
Tetralogy of Fallot	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2017	RCV000577944.2
Atrial septal defect 2	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2017	RCV000577946.2
Primary dilated cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2017	RCV000578059.2
not provided	Likely benign (7)	criteria provided, multiple submitters, no conflicts	Apr 1, 2024	RCV001529780.20

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 benign (Nov 04, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000594925.1 First in ClinVar: May 29, 2016 Last updated: May 29, 2016
Likely benign (Dec 07, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001788823.1 First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021	Comment: This variant is associated with the following publications: (PMID: 30590232, 30229885, 28381408, 20874241, 24033266, 27374936, 18076106, 18055909, 12939651)
Likely benign (Sep 15, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318063.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Atrioventricular septal defect 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000287300.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Atrioventricular septal defect 4 Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679864.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (4) PubMed: 18076106‚ 20874241‚ 24033266‚ 27374936 Number of individuals with the variant: 1
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary dilated cardiomyopathy Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679865.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (4) PubMed: 18076106‚ 20874241‚ 24033266‚ 27374936 Number of individuals with the variant: 1
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Atrial septal defect 2 Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679863.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (4) PubMed: 18076106‚ 20874241‚ 24033266‚ 27374936 Number of individuals with the variant: 1
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tetralogy of Fallot Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679866.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (4) PubMed: 18076106‚ 20874241‚ 24033266‚ 27374936 Number of individuals with the variant: 1
Uncertain significance (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ventricular septal defect 1 Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679867.1 First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018	Publications: PubMed (4) PubMed: 18076106‚ 20874241‚ 24033266‚ 27374936 Number of individuals with the variant: 1
Likely benign (Apr 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004164377.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: GATA4: BP4, BS2 Number of individuals with the variant: 4
Benign (Apr 07, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000060981.5 First in ClinVar: May 03, 2013 Last updated: May 29, 2016	Comment: p.Cys274Cys in exon 4 of GATA4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue … (more) p.Cys274Cys in exon 4 of GATA4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.3% (202/66414) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs55980825). (less) Number of individuals with the variant: 4
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001932976.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743847.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955233.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002036098.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975912.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
click to load more click to collapse

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

p.Cys274Cys in exon 4 of GATA4: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.3% (202/66414) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs55980825).

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
Analysis of Rare Variants in the Alcohol Dependence Candidate Gene GATA4.	Degenhardt F	Alcoholism, clinical and experimental research	2016	PMID: 27374936
A systematic approach to assessing the clinical significance of genetic variants.	Duzkale H	Clinical genetics	2013	PMID: 24033266
GATA4 mutations in 357 unrelated patients with congenital heart malformation.	Butler TL	Genetic testing and molecular biomarkers	2010	PMID: 20874241
Mutations in GATA4, NKX2.5, CRELD1, and BMP4 are infrequently found in patients with congenital cardiac septal defects.	Posch MG	American journal of medical genetics. Part A	2008	PMID: 18076106

Text-mined citations for rs55980825 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001308093.3(GATA4):c.825C>T (p.Cys275=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs55980825 ...