ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.375C>A (p.Val125=)
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_020975.6(RET):c.375C>A (p.Val125=)
Variation ID: 95997 Accession: VCV000095997.53
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43102379 (GRCh38) [ NCBI UCSC ] 10: 43597827 (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 Mar 24, 2015 May 12, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.375C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Val125= synonymous NM_000323.2:c.375C>A NP_000314.1:p.Val125= synonymous NM_001406743.1:c.375C>A NP_001393672.1:p.Val125= synonymous NM_001406744.1:c.375C>A NP_001393673.1:p.Val125= synonymous NM_001406759.1:c.375C>A NP_001393688.1:p.Val125= synonymous NM_001406760.1:c.375C>A NP_001393689.1:p.Val125= synonymous NM_001406761.1:c.338-92C>A intron variant NM_001406762.1:c.338-92C>A intron variant NM_001406763.1:c.375C>A NP_001393692.1:p.Val125= synonymous NM_001406764.1:c.338-92C>A intron variant NM_001406765.1:c.375C>A NP_001393694.1:p.Val125= synonymous NM_001406766.1:c.337+1657C>A intron variant NM_001406767.1:c.337+1657C>A intron variant NM_001406768.1:c.338-92C>A intron variant NM_001406769.1:c.375C>A NP_001393698.1:p.Val125= synonymous NM_001406770.1:c.337+1657C>A intron variant NM_001406771.1:c.375C>A NP_001393700.1:p.Val125= synonymous NM_001406772.1:c.375C>A NP_001393701.1:p.Val125= synonymous NM_001406773.1:c.375C>A NP_001393702.1:p.Val125= synonymous NM_001406774.1:c.338-92C>A intron variant NM_001406775.1:c.337+1657C>A intron variant NM_001406776.1:c.337+1657C>A intron variant NM_001406777.1:c.337+1657C>A intron variant NM_001406778.1:c.337+1657C>A intron variant NM_001406779.1:c.375C>A NP_001393708.1:p.Val125= synonymous NM_001406780.1:c.375C>A NP_001393709.1:p.Val125= synonymous NM_001406781.1:c.375C>A NP_001393710.1:p.Val125= synonymous NM_001406782.1:c.375C>A NP_001393711.1:p.Val125= synonymous NM_001406783.1:c.338-92C>A intron variant NM_001406784.1:c.74-6652C>A intron variant NM_001406785.1:c.375C>A NP_001393714.1:p.Val125= synonymous NM_001406786.1:c.338-92C>A intron variant NM_001406787.1:c.375C>A NP_001393716.1:p.Val125= synonymous NM_001406788.1:c.337+1657C>A intron variant NM_001406789.1:c.337+1657C>A intron variant NM_001406790.1:c.337+1657C>A intron variant NM_001406791.1:c.337+1657C>A intron variant NM_001406792.1:c.74-9720C>A intron variant NM_001406793.1:c.74-9720C>A intron variant NM_001406794.1:c.74-9720C>A intron variant NM_020629.2:c.375C>A NP_065680.1:p.Val125= synonymous NM_020630.7:c.375C>A NP_065681.1:p.Val125= synonymous NC_000010.11:g.43102379C>A NC_000010.10:g.43597827C>A NG_007489.1:g.30311C>A LRG_518:g.30311C>A LRG_518t1:c.375C>A LRG_518p1:p.Val125= LRG_518t2:c.375C>A LRG_518p2:p.Val125= - Protein change
- Other names
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- Canonical SPDI
- NC_000010.11:43102378:C: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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0.00539 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00877
The Genome Aggregation Database (gnomAD) 0.00877
Trans-Omics for Precision Medicine (TOPMed) 0.00900
1000 Genomes Project 30x 0.00500
1000 Genomes Project 0.00539
Exome Aggregation Consortium (ExAC) 0.00671
The Genome Aggregation Database (gnomAD), exomes 0.00736
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
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. |
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RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3522 | 3642 |
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. |
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Benign (8) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000082057.32 | |
Benign (1) |
criteria provided, single submitter
|
Nov 25, 2014 | RCV000163272.11 | |
Benign (1) |
criteria provided, single submitter
|
Jan 13, 2018 | RCV000267055.13 | |
Benign (1) |
criteria provided, single submitter
|
Jan 13, 2018 | RCV000307088.13 | |
Likely benign (1) |
criteria provided, single submitter
|
Jan 13, 2018 | RCV000364069.13 | |
Benign (1) |
criteria provided, single submitter
|
Jan 13, 2018 | RCV000407158.13 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2024 | RCV000712298.30 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV001082716.16 | |
Benign (1) |
no assertion criteria provided
|
Jan 1, 2013 | RCV000736271.10 | |
Benign (1) |
criteria provided, single submitter
|
Jul 7, 2023 | RCV003315608.8 |
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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Benign
(May 08, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000514407.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
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Benign
(Oct 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000842761.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
|
|
Benign
(Jan 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000362246.3
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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
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Likely benign
(Jan 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Renal hypodysplasia/aplasia 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000362248.3
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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
|
|
Benign
(Jan 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Pheochromocytoma
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000362249.3
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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
Benign
(Jan 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000362247.3
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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
Benign
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2B
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004017345.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
|
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Benign
(Sep 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004357217.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
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Benign
(Nov 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001472115.2
First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024 |
|
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Benign
(Nov 25, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000213800.7
First in ClinVar: Mar 24, 2015 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
(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: SCV002497022.13
First in ClinVar: Apr 11, 2022 Last updated: May 12, 2024 |
Comment:
RET: BS1, BS2
Number of individuals with the variant: 69
|
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Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000313728.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
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Benign
(Aug 20, 2012)
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criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000113996.8
First in ClinVar: Jan 17, 2014 Last updated: Mar 08, 2017 |
Number of individuals with the variant: 2
Sex: mixed
|
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Benign
(Feb 21, 2013)
|
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: SCV000967108.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
Val125Val in exon 3 of RET: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue … (more)
Val125Val in exon 3 of RET: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 1.2% (102/8600) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1800859). (less)
Number of individuals with the variant: 1
|
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Benign
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760461.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
|
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Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000153976.13
First in ClinVar: Jun 09, 2014 Last updated: Feb 20, 2024 |
|
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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: SCV001808562.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
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Benign
(Jan 01, 2013)
|
no assertion criteria provided
Method: research
|
Hirschsprung disease
Affected status: yes
Allele origin:
unknown
|
Human Genomics Unit, Institute for molecular medicine Finland (FIMM)
Accession: SCV000864568.1
First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019 |
Number of individuals with the variant: 2
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742013.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
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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: SCV001956008.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Chinese patients with sporadic Hirschsprung's disease are predominantly represented by a single RET haplotype. | Garcia-Barceló MM | Journal of medical genetics | 2003 | PMID: 14627689 |
Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression. | Borrego S | Journal of medical genetics | 1999 | PMID: 10528857 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RET | - | - | - | - |
Text-mined citations for rs1800859 ...
HelpRecord last updated May 12, 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.