ClinVar Genomic variation as it relates to human health
NM_000514.4(GDNF):c.277C>T (p.Arg93Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000514.4(GDNF):c.277C>T (p.Arg93Trp)
Variation ID: 8758 Accession: VCV000008758.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5p13.2 5: 37816010 (GRCh38) [ NCBI UCSC ] 5: 37816112 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Apr 15, 2024 Jan 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000514.4:c.277C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000505.1:p.Arg93Trp missense NM_001190468.1:c.328C>T NP_001177397.1:p.Arg110Trp missense NM_001190469.1:c.250C>T NP_001177398.1:p.Arg84Trp missense NM_001278098.1:c.121C>T NP_001265027.1:p.Arg41Trp missense NM_199231.2:c.199C>T NP_954701.1:p.Arg67Trp missense NC_000005.10:g.37816010G>A NC_000005.9:g.37816112G>A NG_011675.2:g.28671C>T P39905:p.Arg93Trp - Protein change
- R93W, R110W, R41W, R84W, R67W
- Other names
- -
- Canonical SPDI
- NC_000005.10:37816009:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00100 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00100
1000 Genomes Project 30x 0.00125
Exome Aggregation Consortium (ExAC) 0.00221
The Genome Aggregation Database (gnomAD), exomes 0.00225
The Genome Aggregation Database (gnomAD) 0.00272
Trans-Omics for Precision Medicine (TOPMed) 0.00289
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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GDNF | - | - |
GRCh38 GRCh37 |
110 | 135 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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. |
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Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Apr 3, 2022 | RCV000009301.9 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 10, 2014 | RCV000150719.5 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 23, 2024 | RCV002512938.8 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 22, 2021 | RCV003934815.1 |
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. |
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Likely benign
(Sep 10, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198137.4
First in ClinVar: Jan 30, 2015 Last updated: Jan 30, 2015 |
Comment:
Arg110Trp in exon 3 of GDNF: This variant has been reported in individuals with various phenotypes including pulmonary presentations (see below). However, it i s … (more)
Arg110Trp in exon 3 of GDNF: This variant has been reported in individuals with various phenotypes including pulmonary presentations (see below). However, it i s not expected to cause disease on its own because it has been identified in 0.3 % (28/8600) of European American chromosomes by the NHLBI Exome Sequencing Proje ct (http://evs.gs.washington.edu/EVS/; dbSNP rs36119840). Phenotypes of individu als reported to carry this variant include isolated congenital central hypoventi lation syndrome, sporadic pheochromocytoma, Hirschsprung disease, and congenital anomalies of the kidney or urinary tract (reported as Arg93Trp; Angrist 1996, S olomon 1996, Woodward 1997, Amiel 1998, Amiel 2003, Chatterjee 2012). In vitro f unctional studies provide some evidence that the Arg110Trp variant may not impac t protein function (reported as Arg93Trp; Eketjall 2002). In summary, this varia nt is not expected to be disease-causing when seen in isolation, though a modify ing role cannot be fully excluded. (less)
Number of individuals with the variant: 1
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Likely benign
(Apr 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810037.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely benign
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003473683.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
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Likely benign
(Apr 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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GDNF-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004755575.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 3
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001316513.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Oct 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004011589.6
First in ClinVar: Jul 16, 2023 Last updated: Apr 15, 2024 |
Comment:
GDNF: BS2
Number of individuals with the variant: 4
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risk factor
(Apr 01, 2003)
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no assertion criteria provided
Method: literature only
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HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029519.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 17, 2021 |
Comment on evidence:
In 1 of 106 unrelated patients with Hirschsprung disease (HSCR3; 613711), Angrist et al. (1996) identified a heterozygous 277C-T transition in exon 2 of the … (more)
In 1 of 106 unrelated patients with Hirschsprung disease (HSCR3; 613711), Angrist et al. (1996) identified a heterozygous 277C-T transition in exon 2 of the GDNF gene, resulting in an arg93-to-trp (R93W) substitution. The patient also carried a mutation in the RET gene (164761). The GDNF mutation was inherited from the patient's unaffected father. The patient had short-segment HSCR and malrotation of the gut. In a large family segregating HSCR, Salomon et al. (1996) identified the R93W mutation in 2 affected individuals and in 1 individual with severe constipation; these 3 patients also carried RET mutations. However, 4 unaffected family members also had both the R93W and RET mutations, and 2 affected family members did not have the R93W mutation. The mutation was not identified in 180 control chromosomes. Salomon et al. (1996) concluded that while GDNF mutations are not sufficient to cause HSCR, they may modulate disease susceptibility or phenotype, especially when present with RET mutations. Exclusion Studies Amiel et al. (1998) identified the R93W mutation in a male patient with congenital central hypoventilation syndrome (209880) and growth hormone deficiency (see 139250), but Amiel et al. (2003) showed that this patient also carried the pathogenic polyalanine expansion in the PHOX2B gene (603851.0001). (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations. | Chatterjee R | Human genetics | 2012 | PMID: 22729463 |
Common variants of the glial cell-derived neurotrophic factor gene do not influence kidney size of the healthy newborn. | Zhang Z | Pediatric nephrology (Berlin, Germany) | 2009 | PMID: 19184120 |
Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. | Amiel J | Nature genetics | 2003 | PMID: 12640453 |
Functional characterization of mutations in the GDNF gene of patients with Hirschsprung disease. | Eketjäll S | Human molecular genetics | 2002 | PMID: 11823451 |
GDNF as a candidate modifier in a type 1 neurofibromatosis (NF1) enteric phenotype. | Bahuau M | Journal of medical genetics | 2001 | PMID: 11565554 |
Mutations of the RET-GDNF signaling pathway in Ondine's curse. | Amiel J | American journal of human genetics | 1998 | PMID: 9497256 |
Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. | Woodward ER | Human molecular genetics | 1997 | PMID: 9215674 |
Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. | Salomon R | Nature genetics | 1996 | PMID: 8896569 |
Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. | Angrist M | Nature genetics | 1996 | PMID: 8896568 |
Text-mined citations for rs36119840 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.