VCV000044334.33 - ClinVar

NM_001308093.3(GATA4):c.1132A>G (p.Ser378Gly)

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.

(12)

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(1); Benign(5)

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.1132A>G (p.Ser378Gly)

Variation ID: 44334 Accession: VCV000044334.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p23.1 8: 11757066 (GRCh38) [ NCBI UCSC ] 8: 11614575 (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 9, 2014	May 1, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001308093.3:c.1132A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001295022.1:p.Ser378Gly	missense
NM_001308094.2:c.511A>G	NP_001295023.1:p.Ser171Gly	missense
NM_001374273.1:c.511A>G	NP_001361202.1:p.Ser171Gly	missense
NM_001374274.1:c.385A>G	NP_001361203.1:p.Ser129Gly	missense
NM_002052.5:c.1129A>G	NP_002043.2:p.Ser377Gly	missense
NC_000008.11:g.11757066A>G
NC_000008.10:g.11614575A>G
NG_008177.2:g.85148A>G
	P43694:p.Ser377Gly

... more HGVS ... less HGVS

Protein change

S377G, S378G, S171G, S129G

Other names

Canonical SPDI

NC_000008.11:11757065:A:G

Functional
consequence

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

Global minor allele
frequency (GMAF)

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.

0.04293 (G)

Allele frequency

The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.07830

The Genome Aggregation Database (gnomAD) 0.09064

The Genome Aggregation Database (gnomAD), exomes 0.09520

Exome Aggregation Consortium (ExAC) 0.09621

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.10057

1000 Genomes Project 30x 0.04154

1000 Genomes Project 0.04293

Links

ClinGen: CA133993

UniProtKB: P43694#VAR_038196

dbSNP: rs3729856

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	795	917

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 (6)	criteria provided, single submitter	Dec 13, 2016	RCV000037322.20
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Nov 7, 2023	RCV000128527.21
Atrioventricular septal defect 4	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001517975.14
Neonatal insulin-dependent diabetes mellitus	Uncertain significance (1)	criteria provided, single submitter	-	RCV002463624.8
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Jun 23, 2015	RCV000620305.11

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.
Benign (Dec 13, 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: SCV000060979.5 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Comment: p.Ser377Gly in exon 6 of GATA4: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus … (more) p.Ser377Gly in exon 6 of GATA4: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus sequence. It h as been identified in 14% (927/6596) of European chromosomes, including 67 homoz ygotes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs3729856). (less) Number of individuals with the variant: 13
Uncertain significance (-)	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1) Method: research	Neonatal insulin-dependent diabetes mellitus Affected status: unknown Allele origin: unknown	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV002605214.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Publications: PubMed (4) PubMed: 20854389‚ 24696446‚ 33865372‚ 27810688 Comment: Potent mutations in GATA4 gene are associated with neonatal diabetes, decreased insulin production due to pancreatic aplasia or hypoplasia. Also associated with isolated cardiac abnormalities … (more) Potent mutations in GATA4 gene are associated with neonatal diabetes, decreased insulin production due to pancreatic aplasia or hypoplasia. Also associated with isolated cardiac abnormalities in children, like atrial septal defects. However no sufficient evidence is found to ascertain the role of this particular variant rs3729856 yet. (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	Invitae Accession: SCV001726593.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024
Benign (Jun 23, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000735049.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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 (Sep 11, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001839278.1 First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021	Comment: This variant is associated with the following publications: (PMID: 30229885, 28541271, 23626780, 28161810, 27064867)
Benign (Nov 07, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002049178.4 First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024
probable-pathogenic (-)	no assertion criteria provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Molecular Genetics and Enzymology, National Research Centre Accession: SCV000172172.1 First in ClinVar: Jul 09, 2014 Last updated: Jul 09, 2014 Comment: Ventricular and atrial septal defects, and pulmonary stenosis	Comment: Converted during submission to Likely pathogenic.
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807583.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001931150.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001952624.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001551693.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001975449.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
click to load more click to collapse

Comment:

p.Ser377Gly in exon 6 of GATA4: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus sequence. It h as been identified in 14% (927/6596) of European chromosomes, including 67 homoz ygotes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs3729856).

Comment:

Potent mutations in GATA4 gene are associated with neonatal diabetes, decreased insulin production due to pancreatic aplasia or hypoplasia. Also associated with isolated cardiac abnormalities in children, like atrial septal defects. However no sufficient evidence is found to ascertain the role of this particular variant rs3729856 yet.

Comment:

This alteration is classified as 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.

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
Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus.	Ding L	BMC endocrine disorders	2021	PMID: 33865372
Clinical whole exome sequencing in early onset diabetes patients.	Kwak SH	Diabetes research and clinical practice	2016	PMID: 27810688
GATA4 mutations are a cause of neonatal and childhood-onset diabetes.	Shaw-Smith C	Diabetes	2014	PMID: 24696446
Genetic investigation in an Italian child with an unusual association of atrial septal defect, attributable to a new familial GATA4 gene mutation, and neonatal diabetes due to pancreatic agenesis.	D'Amato E	Diabetic medicine : a journal of the British Diabetic Association	2010	PMID: 20854389

Text-mined citations for rs3729856 ...

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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001308093.3(GATA4):c.1132A>G (p.Ser378Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs3729856 ...