GDF1

protein-coding

growth differentiation factor 1, the group of Transforming growth factor beta superfamily

Gene summary

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. Studies in rodents suggest that this protein is involved in the establishment of left-right asymmetry in early embryogenesis and in neural development in later embryogenesis. The encoded protein is translated from a bicistronic mRNA that also encodes ceramide synthase 1. Mutations in this gene are associated with several congenital cardiovascular malformations. [provided by RefSeq, Jul 2016]

MANE transcript

NM_001492.6

Inheritance

AR, AD

ClinVar variants

P:39U:136B:75

Top phenotype

Congenital heart defects, multiple types, 6; Right atrial isomerism

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr19:18,868,545-18,896,158

External References & Databases

Ensembl (ENSG00000130283)

Transcript & Mutation Effects

hg38 • Region Span ~27.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

right atrial isomerismLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008832

Submitter: Ambry Genetics

congenital heart defects, multiple types, 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013463

Submitter: Ambry Genetics

right atrial isomerismSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008832

Submitter: Labcorp Genetics (formerly Invitae)

congenital heart defects, multiple types, 6NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0013463

Submitter: Illumina

conotruncal heart malformationsLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0016581

Submitter: Labcorp Genetics (formerly Invitae)

congenital heart defects, multiple types, 6DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013463

Submitter: G2P

congenital heart defects, multiple types, 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013463

Submitter: PanelApp Australia

right atrial isomerismSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008832

Submitter: Orphanet

right atrial isomerismSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008832

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Congenital heart defects, multiple types, 6; Right atrial isomerismAD/AR

Manifestation: Cardiovascular; Gastrointestinal; Pulmonary

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 17924340; 20413652; 28991257

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GDF1 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 172

not specifiedTotal: 91

Progressive myoclonic epilepsy type 8Total: 68

GDF1-related disorderTotal: 27

Congenital heart defects, multiple types, 6Total: 19

Right atrial isomerismTotal: 16

GDF1-RELATED DISORDERSTotal: 10

Inborn genetic diseasesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001492.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	66 clinvar		68
missense		6 clinvar	126 clinvar	9 clinvar		141
nonsense	3 clinvar	8 clinvar	2 clinvar			13
start loss						0
frameshift	7 clinvar	15 clinvar	4 clinvar			26
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	10	29	136	75	0	250

Highest pathogenic variant AF is 0.0009427863

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001492.6	RefSeq	NP_001483.3	2	MANE Select
ENST00000247005.8	Ensembl	ENSP00000247005.5	2	MANE Select
NM_001387438.1	RefSeq	NP_001374367.1	2	Standard
ENST00001037983.1	Ensembl	ENSP00000707800.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TGF-Core
Metabolism of lipids
Metabolism
ceramide <i>de novo</i> biosynthesis
Sphingolipid de novo biosynthesis

Biological Process

regulation of signaling receptor activity
positive regulation of pathway-restricted SMAD protein phosphorylation
BMP signaling pathway
regulation of apoptotic process
regulation of MAPK cascade

Molecular Function

cytokine activity
transforming growth factor beta receptor binding
growth factor activity

Cellular Component

extracellular space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000247005
Coding exons: 2
Length: 27545
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.69	102	163	0.626	0.0000121	2207
Missense (PolyPhen)		39	69.186	0.5637		836
Synonymous	1.95	59	81.4	0.725	0.00000681	889
Loss of Function	1.70	1	5.17	0.194	2.61e-7	72

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May mediate cell differentiation events during embryonic development.;
Disease: DISEASE: Congenital heart defects, multiple types, 6 (CHTD6) [MIM:613854]: An autosomal dominant disorder characterized by congenital developmental abnormalities involving structures of the heart. Common defects include tetralogy of Fallot, transposition of the great arteries, double-outlet right ventricle, total anomalous pulmonary venous return, pulmonary stenosis or atresia, atrioventricular canal, ventricular septal defect, and hypoplastic left or right ventricle. {ECO:0000269|PubMed:17924340, ECO:0000269|PubMed:28991257}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tetralogy of Fallot (TOF) [MIM:187500]: A congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. In this condition, blood from both ventricles (oxygen-rich and oxygen-poor) is pumped into the body often causing cyanosis. {ECO:0000269|PubMed:17924340}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Right atrial isomerism (RAI) [MIM:208530]: A severe complex congenital heart defect resulting from embryonic disruption of proper left-right axis determination. RAI is usually characterized by complete atrioventricular septal defect with a common atrium and univentricular AV connection, total anomalous pulmonary drainage, and transposition or malposition of the great arteries. Affected individuals present at birth with severe cardiac failure. Other associated abnormalities include bilateral trilobed lungs, midline liver, and asplenia, as well as situs inversus affecting other organs. {ECO:0000269|PubMed:20413652, ECO:0000269|PubMed:28991257}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.121

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium