p.Ser395Asn in exon 5 of EDNRB: This variant is not expected to have clinical si gnificance because it has been identified in 1.4% (119/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs5352).
ClinVar Genomic variation as it relates to human health
NM_001122659.3(EDNRB):c.914G>A (p.Ser305Asn)
Germline
Classification
Help
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)
Help
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(8); Likely benign(2)
Uncertain significance(1); Benign(8); Likely benign(2)
12
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001122659.3(EDNRB):c.914G>A (p.Ser305Asn)
Variation ID: 16638 Accession: VCV000016638.31
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q22.3 13: 77901095 (GRCh38) [ NCBI UCSC ] 13: 78475230 (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 Oct 2, 2016 Oct 20, 2024 Apr 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001122659.3:c.914G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001116131.1:p.Ser305Asn missense NM_000115.5:c.914G>A NP_000106.1:p.Ser305Asn missense NM_001201397.2:c.1184G>A NP_001188326.1:p.Ser395Asn missense NM_003991.4:c.914G>A NP_003982.1:p.Ser305Asn missense NC_000013.11:g.77901095C>T NC_000013.10:g.78475230C>T NG_011630.3:g.78629G>A P24530:p.Ser305Asn - Protein change
- S305N, S395N
- Other names
- -
- Canonical SPDI
- NC_000013.11:77901094:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00499 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00499
1000 Genomes Project 30x 0.00562
Exome Aggregation Consortium (ExAC) 0.00891
Trans-Omics for Precision Medicine (TOPMed) 0.00990
The Genome Aggregation Database (gnomAD), exomes 0.01004
The Genome Aggregation Database (gnomAD) 0.01109
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| EDNRB | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
91 | 381 | |
| EDNRB-AS1 | - | - | - | GRCh38 | - | 232 |
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. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, single submitter
|
Mar 6, 2018 | RCV000018118.8 | |
| Benign (3) |
criteria provided, multiple submitters, no conflicts
|
May 10, 2017 | RCV000222856.14 | |
| Likely benign (1) |
criteria provided, single submitter
|
Mar 1, 2017 | RCV000626404.2 | |
| Likely benign (1) |
criteria provided, single submitter
|
Nov 1, 2016 | RCV000659497.1 | |
| Benign (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2024 | RCV000954472.20 | |
| Benign (1) |
criteria provided, single submitter
|
- | RCV001258252.2 |
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
(Mar 01, 2017)
|
criteria provided, single submitter
Method: research
|
Waardenburg syndrome type 2A
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Laboratory of Human Genetics, Universidade de São Paulo
Accession: SCV000678739.1
First in ClinVar: May 06, 2018 Last updated: May 06, 2018 |
Geographic origin: Brazil
|
|
|
Likely benign
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Waardenburg syndrome type 4A
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781315.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
|
|
|
Benign
(May 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000707740.2
First in ClinVar: Oct 02, 2016 Last updated: Apr 09, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Benign
(Jan 13, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000269066.2
First in ClinVar: May 29, 2016 Last updated: Apr 09, 2018 |
Comment:
p.Ser395Asn in exon 5 of EDNRB: This variant is not expected to have clinical si gnificance because it has been identified in 1.4% (119/8600) of … (more)
p.Ser395Asn in exon 5 of EDNRB: This variant is not expected to have clinical si gnificance because it has been identified in 1.4% (119/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs5352). (less)
Number of individuals with the variant: 18
|
|
|
Benign
(-)
|
criteria provided, single submitter
Method: research
|
Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001435166.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The heterozygous p.Ser305Asn variant, sometimes called p.Ser205Asn or p.Ser295Asn, in EDNRB has been identified in at least 6 individuals with Hirschsprung disease, including 4 relatives … (more)
The heterozygous p.Ser305Asn variant, sometimes called p.Ser205Asn or p.Ser295Asn, in EDNRB has been identified in at least 6 individuals with Hirschsprung disease, including 4 relatives from 1 family (PMID: 8852659, 10874640, 22995991). However, this variant does not segregate with disease (PMID: 10874640), and has been identified in >2% of European (Finnish) chromosomes and 5 homozygotes in ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for Hirschsprung disease. (less)
|
|
|
Benign
(May 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000727101.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
This variant is associated with the following publications: (PMID: 22995991, 26764160, 27535533, 10874640, 8852659, 21507037)
|
|
|
Benign
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001101107.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Apr 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004133216.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
EDNRB: BS1, BS2
Number of individuals with the variant: 5
|
|
|
Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000302327.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
|
Benign
(Dec 29, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV001143835.1
First in ClinVar: Jan 18, 2020 Last updated: Jan 18, 2020 |
|
|
|
Uncertain significance
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hirschsprung disease, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000384810.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
|
|
|
risk factor
(Apr 01, 1999)
|
no assertion criteria provided
Method: literature only
|
HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038397.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017 |
Comment on evidence:
In a patient with Hirschsprung disease (600155), Auricchio et al. (1999) found double heterozygosity for a silent mutation, I647I, of the RET gene (164761.0037), inherited … (more)
In a patient with Hirschsprung disease (600155), Auricchio et al. (1999) found double heterozygosity for a silent mutation, I647I, of the RET gene (164761.0037), inherited from the unaffected mother, and an EDNRB missense mutation, S305N, transmitted by the healthy father. In 2 different patients they demonstrated both in vivo and in vitro that the silent RET mutation can interfere with correct transcription, possibly leading to a reduced level of the RET protein. The coexistence in the same patient of 2 functionally significant EDNRB and RET mutations suggested a direct genetic interaction between these 2 distinct transmembrane receptors in polygenic HSCR disease. Lek et al. (2016) questioned the validity of this variant as a susceptibility allele because it has a high global allele frequency (0.0089) in the ExAC database. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
The heterozygous p.Ser305Asn variant, sometimes called p.Ser205Asn or p.Ser295Asn, in EDNRB has been identified in at least 6 individuals with Hirschsprung disease, including 4 relatives from 1 family (PMID: 8852659, 10874640, 22995991). However, this variant does not segregate with disease (PMID: 10874640), and has been identified in >2% of European (Finnish) chromosomes and 5 homozygotes in ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for Hirschsprung disease.
Comment:
This variant is associated with the following publications: (PMID: 22995991, 26764160, 27535533, 10874640, 8852659, 21507037)
Comment:
EDNRB: BS1, BS2
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
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:
p.Ser395Asn in exon 5 of EDNRB: This variant is not expected to have clinical si gnificance because it has been identified in 1.4% (119/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs5352).
Comment:
The heterozygous p.Ser305Asn variant, sometimes called p.Ser205Asn or p.Ser295Asn, in EDNRB has been identified in at least 6 individuals with Hirschsprung disease, including 4 relatives from 1 family (PMID: 8852659, 10874640, 22995991). However, this variant does not segregate with disease (PMID: 10874640), and has been identified in >2% of European (Finnish) chromosomes and 5 homozygotes in ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for Hirschsprung disease.
Comment:
This variant is associated with the following publications: (PMID: 22995991, 26764160, 27535533, 10874640, 8852659, 21507037)
Comment:
EDNRB: BS1, BS2
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Waardenburg syndrome: Novel mutations in a large Brazilian sample. | Bocángel MAP | European journal of medical genetics | 2018 | PMID: 29407415 |
| Analysis of protein-coding genetic variation in 60,706 humans. | Lek M | Nature | 2016 | PMID: 27535533 |
| An informatics approach to analyzing the incidentalome. | Berg JS | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22995991 |
| EDNRB gene variants and melanoma risk in two southern European populations. | Spica T | Clinical and experimental dermatology | 2011 | PMID: 21507037 |
| A new experimental approach is required in the molecular analysis of intestinal neuronal dysplasia type B patients. | Sánchez-Mejías A | Experimental and therapeutic medicine | 2010 | PMID: 22993632 |
| New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease. | Sánchez-Mejías A | Genetics in medicine : official journal of the American College of Medical Genetics | 2010 | PMID: 20009762 |
| Pigmentation-related genes and their implication in malignant melanoma susceptibility. | Fernandez LP | Experimental dermatology | 2009 | PMID: 19320733 |
| Re: Association between endothelin receptor B nonsynonymous variants and melanoma risk. | Thirumaran RK | Journal of the National Cancer Institute | 2006 | PMID: 16954478 |
| Association between endothelin receptor B nonsynonymous variants and melanoma risk. | Soufir N | Journal of the National Cancer Institute | 2005 | PMID: 16145050 |
| A consanguineous family with Hirschsprung disease, microcephaly, and mental retardation (Goldberg-Shprintzen syndrome). | Brooks AS | Journal of medical genetics | 1999 | PMID: 10874640 |
| Double heterozygosity for a RET substitution interfering with splicing and an EDNRB missense mutation in Hirschsprung disease. | Auricchio A | American journal of human genetics | 1999 | PMID: 10090908 |
| Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. | Auricchio A | Human molecular genetics | 1996 | PMID: 8852659 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EDNRB | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs5352 ...
HelpThese 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
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.