GDNF

glial cell derived neurotrophic factor, the group of GDNF family ligands

Basic information

Region (hg38): 5:37812676-37840041

Links

ENSG00000168621 ∙ NCBI:2668 ∙ OMIM:600837 ∙ HGNC:4232 ∙ Uniprot:P39905 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Central hypoventilation syndrome; Hirschsprung disease, susceptibility to, 3	AD	Gastrointestinal; Neurologic	In Central hypoventilation syndrome, early recognition and interventions to support ventilation (as well as avoidance of exacerbating factors) can reduce morbidity and mortality; In conditions that may involve Hirschsprung disease, recognition of potential GI anomalies (eg, aganglionosis) may allow prompt recognition and treatment	Gastrointestinal; Neurologic	8896568; 8968758; 8896569; 9497256; 11973622; 11823451; 22729463

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GDNF gene.

• Hirschsprung disease, susceptibility to, 3 (85 variants)
• not provided (19 variants)
• not specified (6 variants)
• Hirschsprung Disease, Dominant (5 variants)
• Inborn genetic diseases (5 variants)
• GDNF-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GDNF gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				4	1	5
missense			10	4		14
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			46	14	24	84
Total	0	0	56	22	25

Variants in GDNF

This is a list of pathogenic ClinVar variants found in the GDNF region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-37812768-C-T		Hirschsprung disease, susceptibility to, 3	Benign (Jan 13, 2018)
5-37812820-GGT-G		Hirschsprung Disease, Dominant	Uncertain significance (Jun 14, 2016)
5-37812823-A-T		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
5-37812938-C-T		Hirschsprung disease, susceptibility to, 3	Benign (Jan 12, 2018)
5-37813000-G-C		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
5-37813005-G-C		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 12, 2018)
5-37813008-G-A		Hirschsprung disease, susceptibility to, 3	Benign (Jan 13, 2018)
5-37813095-A-T		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
5-37813205-C-T		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 12, 2018)
5-37813211-C-T		Hirschsprung disease, susceptibility to, 3	Likely benign (Apr 27, 2017)
5-37813333-C-T		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
5-37813384-C-T		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
5-37813386-A-G		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
5-37813438-C-T		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 12, 2018)
5-37813447-C-A		Hirschsprung disease, susceptibility to, 3	Benign (Jan 13, 2018)
5-37813489-C-A		Hirschsprung disease, susceptibility to, 3	Benign (Jan 13, 2018)
5-37813501-A-C		Hirschsprung disease, susceptibility to, 3	Likely benign (Jan 13, 2018)
5-37813532-G-C		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Apr 27, 2017)
5-37813583-TG-T		Hirschsprung Disease, Dominant	Uncertain significance (Jun 14, 2016)
5-37813592-G-A		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 12, 2018)
5-37813637-C-T		Hirschsprung disease, susceptibility to, 3	Likely benign (Jan 12, 2018)
5-37813724-G-A		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 12, 2018)
5-37813753-G-T		Hirschsprung disease, susceptibility to, 3	Benign (Jan 12, 2018)
5-37813863-C-T		Hirschsprung disease, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
5-37813866-C-A		Hirschsprung disease, susceptibility to, 3	Benign (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GDNF	protein_coding	protein_coding	ENST00000427982	3	27010

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.203	0.757	123085	0	1	123086	0.00000406

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.10	100	136	0.735	0.00000741	1483
Missense in Polyphen		22	45.424	0.48432		544
Synonymous	-0.973	67	57.6	1.16	0.00000343	459
Loss of Function	1.72	2	6.86	0.292	2.89e-7	97

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.0000328	0.0000328
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake. {ECO:0000269|PubMed:8493557}.
• Disease: DISEASE: Hirschsprung disease 3 (HSCR3) [MIM:613711]: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. {ECO:0000269|PubMed:10917288, ECO:0000269|PubMed:8896568, ECO:0000269|PubMed:8896569, ECO:0000269|PubMed:8968758}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Congenital central hypoventilation syndrome (CCHS) [MIM:209880]: Rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. {ECO:0000269|PubMed:9497256}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pheochromocytoma (PCC) [MIM:171300]: A catecholamine- producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. {ECO:0000269|PubMed:9215674}. Note=The gene represented in this entry may act as a disease modifier.
• Pathway: Allograft Rejection;Spinal Cord Injury;Developmental Biology;Signal Transduction;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;NCAM signaling for neurite out-growth;Posttranslational regulation of adherens junction stability and dissassembly;Signaling events regulated by Ret tyrosine kinase;NCAM1 interactions;RET signaling;Axon guidance;GPCR signaling-G alpha i (Consensus)

Recessive Scores

• pRec: 0.714

Intolerance Scores

• loftool: 0.0280
• rvis_EVS: 0.19
• rvis_percentile_EVS: 66.82

Haploinsufficiency Scores

• pHI: 0.710
• hipred: Y
• hipred_score: 0.751
• ghis: 0.432

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.673

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gdnf
• Phenotype: digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); immune system phenotype; renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); endocrine/exocrine gland phenotype; muscle phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: gdnfa
• Affected structure: afferent neuron
• Phenotype tag: abnormal
• Phenotype quality: truncated

Gene ontology

• Biological process: MAPK cascade;metanephros development;branching involved in ureteric bud morphogenesis;neural crest cell migration;organ induction;postsynaptic membrane organization;mesenchymal to epithelial transition involved in metanephros morphogenesis;signal transduction;nervous system development;axon guidance;positive regulation of cell population proliferation;adult locomotory behavior;regulation of gene expression;regulation of signaling receptor activity;dorsal spinal cord development;postganglionic parasympathetic fiber development;peristalsis;neuron projection development;positive regulation of monooxygenase activity;positive regulation of dopamine secretion;negative regulation of apoptotic process;negative regulation of neuron apoptotic process;positive regulation of cell differentiation;positive regulation of transcription by RNA polymerase II;mRNA stabilization;enteric nervous system development;sympathetic nervous system development;embryonic organ development;regulation of dopamine uptake involved in synaptic transmission;ureteric bud formation;regulation of morphogenesis of a branching structure;chemoattraction of axon;commissural neuron axon guidance;positive regulation of ureteric bud formation;positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis;positive regulation of branching involved in ureteric bud morphogenesis;regulation of stem cell differentiation;negative regulation of extrinsic apoptotic signaling pathway in absence of ligand;regulation of semaphorin-plexin signaling pathway
• Cellular component: extracellular region
• Molecular function: Ras guanyl-nucleotide exchange factor activity;signaling receptor binding;protein binding;growth factor activity;protein homodimerization activity;chemoattractant activity involved in axon guidance