The RET c.2996C>G (p.Ala999Gly) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type II. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2996C>G (p.Ala999Gly)
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.
(2)
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.
Uncertain significance
2
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.2996C>G (p.Ala999Gly)
Variation ID: 2503515 Accession: VCV002503515.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43124939 (GRCh38) [ NCBI UCSC ] 10: 43620387 (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 4, 2023 Nov 20, 2023 Jul 16, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.2996C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Ala999Gly missense NM_000323.2:c.2996C>G NP_000314.1:p.Ala999Gly missense NM_001355216.2:c.2234C>G NP_001342145.1:p.Ala745Gly missense NM_001406743.1:c.2996C>G NP_001393672.1:p.Ala999Gly missense NM_001406744.1:c.2996C>G NP_001393673.1:p.Ala999Gly missense NM_001406759.1:c.2996C>G NP_001393688.1:p.Ala999Gly missense NM_001406760.1:c.2996C>G NP_001393689.1:p.Ala999Gly missense NM_001406761.1:c.2867C>G NP_001393690.1:p.Ala956Gly missense NM_001406762.1:c.2867C>G NP_001393691.1:p.Ala956Gly missense NM_001406763.1:c.2861C>G NP_001393692.1:p.Ala954Gly missense NM_001406764.1:c.2867C>G NP_001393693.1:p.Ala956Gly missense NM_001406765.1:c.2861C>G NP_001393694.1:p.Ala954Gly missense NM_001406766.1:c.2708C>G NP_001393695.1:p.Ala903Gly missense NM_001406767.1:c.2708C>G NP_001393696.1:p.Ala903Gly missense NM_001406768.1:c.2732C>G NP_001393697.1:p.Ala911Gly missense NM_001406769.1:c.2600C>G NP_001393698.1:p.Ala867Gly missense NM_001406770.1:c.2708C>G NP_001393699.1:p.Ala903Gly missense NM_001406771.1:c.2558C>G NP_001393700.1:p.Ala853Gly missense NM_001406772.1:c.2600C>G NP_001393701.1:p.Ala867Gly missense NM_001406773.1:c.2558C>G NP_001393702.1:p.Ala853Gly missense NM_001406774.1:c.2471C>G NP_001393703.1:p.Ala824Gly missense NM_001406775.1:c.2270C>G NP_001393704.1:p.Ala757Gly missense NM_001406776.1:c.2270C>G NP_001393705.1:p.Ala757Gly missense NM_001406777.1:c.2270C>G NP_001393706.1:p.Ala757Gly missense NM_001406778.1:c.2270C>G NP_001393707.1:p.Ala757Gly missense NM_001406779.1:c.2099C>G NP_001393708.1:p.Ala700Gly missense NM_001406780.1:c.2099C>G NP_001393709.1:p.Ala700Gly missense NM_001406781.1:c.2099C>G NP_001393710.1:p.Ala700Gly missense NM_001406782.1:c.2099C>G NP_001393711.1:p.Ala700Gly missense NM_001406783.1:c.1970C>G NP_001393712.1:p.Ala657Gly missense NM_001406784.1:c.2006C>G NP_001393713.1:p.Ala669Gly missense NM_001406785.1:c.1979C>G NP_001393714.1:p.Ala660Gly missense NM_001406786.1:c.1970C>G NP_001393715.1:p.Ala657Gly missense NM_001406787.1:c.1964C>G NP_001393716.1:p.Ala655Gly missense NM_001406788.1:c.1811C>G NP_001393717.1:p.Ala604Gly missense NM_001406789.1:c.1811C>G NP_001393718.1:p.Ala604Gly missense NM_001406790.1:c.1811C>G NP_001393719.1:p.Ala604Gly missense NM_001406791.1:c.1691C>G NP_001393720.1:p.Ala564Gly missense NM_001406792.1:c.1547C>G NP_001393721.1:p.Ala516Gly missense NM_001406793.1:c.1547C>G NP_001393722.1:p.Ala516Gly missense NM_001406794.1:c.1547C>G NP_001393723.1:p.Ala516Gly missense NM_020629.2:c.2996C>G NP_065680.1:p.Ala999Gly missense NM_020630.7:c.2996C>G NP_065681.1:p.Ala999Gly missense NC_000010.11:g.43124939C>G NC_000010.10:g.43620387C>G NG_007489.1:g.52871C>G LRG_518:g.52871C>G LRG_518t1:c.2996C>G LRG_518p1:p.Ala999Gly LRG_518t2:c.2996C>G LRG_518p2:p.Ala999Gly - Protein change
- A516G, A564G, A604G, A655G, A657G, A660G, A669G, A700G, A745G, A757G, A824G, A853G, A867G, A903G, A911G, A954G, A956G, A999G
- Other names
- -
- Canonical SPDI
- NC_000010.11:43124938:C:G
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|||
| RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3593 | 3715 | |
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 (1) |
criteria provided, single submitter
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Mar 31, 2023 | RCV003230330.1 | |
|
RET-related disorder
|
Uncertain significance (1) |
criteria provided, single submitter
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Jul 16, 2023 | RCV004538927.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Mar 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV003928091.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
The RET c.2996C>G (p.Ala999Gly) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but … (more)
The RET c.2996C>G (p.Ala999Gly) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type II. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
|
|
|
Uncertain significance
(Jul 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
RET-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004105594.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The RET c.2996C>G variant is predicted to result in the amino acid substitution p.Ala999Gly. To our knowledge, this variant has not been reported in the … (more)
The RET c.2996C>G variant is predicted to result in the amino acid substitution p.Ala999Gly. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
Comment:
Comment:
The RET c.2996C>G variant is predicted to result in the amino acid substitution p.Ala999Gly. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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:
The RET c.2996C>G (p.Ala999Gly) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type II. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Comment:
The RET c.2996C>G variant is predicted to result in the amino acid substitution p.Ala999Gly. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for this variant ...
HelpRecord last updated Nov 03, 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.