ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.1438G>A (p.Glu480Lys)
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.
Uncertain significance(3); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.1438G>A (p.Glu480Lys)
Variation ID: 135189 Accession: VCV000135189.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43111381 (GRCh38) [ NCBI UCSC ] 10: 43606829 (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 Jun 9, 2014 Feb 14, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.1438G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Glu480Lys missense NM_000323.2:c.1438G>A NP_000314.1:p.Glu480Lys missense NM_001355216.2:c.676G>A NP_001342145.1:p.Glu226Lys missense NM_001406743.1:c.1438G>A NP_001393672.1:p.Glu480Lys missense NM_001406744.1:c.1438G>A NP_001393673.1:p.Glu480Lys missense NM_001406759.1:c.1438G>A NP_001393688.1:p.Glu480Lys missense NM_001406760.1:c.1438G>A NP_001393689.1:p.Glu480Lys missense NM_001406761.1:c.1309G>A NP_001393690.1:p.Glu437Lys missense NM_001406762.1:c.1309G>A NP_001393691.1:p.Glu437Lys missense NM_001406763.1:c.1438G>A NP_001393692.1:p.Glu480Lys missense NM_001406764.1:c.1309G>A NP_001393693.1:p.Glu437Lys missense NM_001406765.1:c.1438G>A NP_001393694.1:p.Glu480Lys missense NM_001406766.1:c.1150G>A NP_001393695.1:p.Glu384Lys missense NM_001406767.1:c.1150G>A NP_001393696.1:p.Glu384Lys missense NM_001406768.1:c.1309G>A NP_001393697.1:p.Glu437Lys missense NM_001406769.1:c.1042G>A NP_001393698.1:p.Glu348Lys missense NM_001406770.1:c.1150G>A NP_001393699.1:p.Glu384Lys missense NM_001406771.1:c.1000G>A NP_001393700.1:p.Glu334Lys missense NM_001406772.1:c.1042G>A NP_001393701.1:p.Glu348Lys missense NM_001406773.1:c.1000G>A NP_001393702.1:p.Glu334Lys missense NM_001406774.1:c.913G>A NP_001393703.1:p.Glu305Lys missense NM_001406775.1:c.712G>A NP_001393704.1:p.Glu238Lys missense NM_001406776.1:c.712G>A NP_001393705.1:p.Glu238Lys missense NM_001406777.1:c.712G>A NP_001393706.1:p.Glu238Lys missense NM_001406778.1:c.712G>A NP_001393707.1:p.Glu238Lys missense NM_001406784.1:c.448G>A NP_001393713.1:p.Glu150Lys missense NM_020629.2:c.1438G>A NP_065680.1:p.Glu480Lys missense NM_020630.7:c.1438G>A NP_065681.1:p.Glu480Lys missense NC_000010.11:g.43111381G>A NC_000010.10:g.43606829G>A NG_007489.1:g.39313G>A LRG_518:g.39313G>A LRG_518t1:c.1438G>A LRG_518p1:p.Glu480Lys LRG_518t2:c.1438G>A LRG_518p2:p.Glu480Lys P07949:p.Glu480Lys - Protein change
- E480K, E226K, E238K, E305K, E348K, E334K, E150K, E384K, E437K
- Other names
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- Canonical SPDI
- NC_000010.11:43111380:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- variation affecting protein Variation Ontology [VariO:0002]
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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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0.00080 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00027
Exome Aggregation Consortium (ExAC) 0.00031
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
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 |
3382 | 3500 |
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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not provided (1) |
no classification provided
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Sep 19, 2013 | RCV000121996.2 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 24, 2024 | RCV000461515.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 4, 2015 | RCV000409013.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000410596.4 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2022 | RCV000570658.3 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Dec 5, 2023 | RCV000758696.4 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 20, 2020 | RCV001650985.3 |
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
(Nov 20, 2020)
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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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GeneDx
Accession: SCV001871024.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31742715, 18280283, 24728327, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31742715, 18280283, 24728327, 12628594, 22174939, 11436122, 26152202) (less)
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Likely benign
(Feb 16, 2022)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002529929.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
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Likely benign
(Jan 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000556199.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2a
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138024.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Dec 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000674799.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: 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)
Number of individuals with the variant: 1
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Uncertain significance
(Dec 04, 2015)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2b
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489735.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Dec 04, 2015)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2a
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489736.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000086207.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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Likely pathogenic
(Feb 22, 2019)
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Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Hirschsprung disease, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS
Accession: SCV000886468.1
First in ClinVar: Mar 11, 2019 Last updated: Mar 11, 2019 |
Clinical Features:
Aganglionic megacolon (present)
Age: 0-9 years
Sex: female
Geographic origin: India
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein
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Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS
Accession: SCV000886468.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients. | So MT | PloS one | 2011 | PMID: 22174939 |
Novel RET mutations in Hirschsprung's disease patients from the diverse South African population. | Julies MG | European journal of human genetics : EJHG | 2001 | PMID: 11436122 |
Text-mined citations for rs537874538 ...
HelpRecord last updated Mar 11, 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.