This sequence change affects codon 804 of the RET mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RET protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 1034965). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2412G>A (p.Val804=)
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.
(3)
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(2); Likely benign(1)
Uncertain significance(2); Likely benign(1)
3
criteria provided, conflicting classifications
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.2412G>A (p.Val804=)
Variation ID: 1034965 Accession: VCV001034965.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43119550 (GRCh38) [ NCBI UCSC ] 10: 43614998 (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 22, 2021 May 1, 2024 Apr 29, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.2412G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Val804= synonymous NM_000323.2:c.2412G>A NP_000314.1:p.Val804= synonymous NM_001355216.2:c.1650G>A NP_001342145.1:p.Val550= synonymous NM_001406743.1:c.2412G>A NP_001393672.1:p.Val804= synonymous NM_001406744.1:c.2412G>A NP_001393673.1:p.Val804= synonymous NM_001406759.1:c.2412G>A NP_001393688.1:p.Val804= synonymous NM_001406760.1:c.2412G>A NP_001393689.1:p.Val804= synonymous NM_001406761.1:c.2283G>A NP_001393690.1:p.Val761= synonymous NM_001406762.1:c.2283G>A NP_001393691.1:p.Val761= synonymous NM_001406763.1:c.2277G>A NP_001393692.1:p.Val759= synonymous NM_001406764.1:c.2283G>A NP_001393693.1:p.Val761= synonymous NM_001406765.1:c.2277G>A NP_001393694.1:p.Val759= synonymous NM_001406766.1:c.2124G>A NP_001393695.1:p.Val708= synonymous NM_001406767.1:c.2124G>A NP_001393696.1:p.Val708= synonymous NM_001406768.1:c.2148G>A NP_001393697.1:p.Val716= synonymous NM_001406769.1:c.2016G>A NP_001393698.1:p.Val672= synonymous NM_001406770.1:c.2124G>A NP_001393699.1:p.Val708= synonymous NM_001406771.1:c.1974G>A NP_001393700.1:p.Val658= synonymous NM_001406772.1:c.2016G>A NP_001393701.1:p.Val672= synonymous NM_001406773.1:c.1974G>A NP_001393702.1:p.Val658= synonymous NM_001406774.1:c.1887G>A NP_001393703.1:p.Val629= synonymous NM_001406775.1:c.1686G>A NP_001393704.1:p.Val562= synonymous NM_001406776.1:c.1686G>A NP_001393705.1:p.Val562= synonymous NM_001406777.1:c.1686G>A NP_001393706.1:p.Val562= synonymous NM_001406778.1:c.1686G>A NP_001393707.1:p.Val562= synonymous NM_001406779.1:c.1515G>A NP_001393708.1:p.Val505= synonymous NM_001406780.1:c.1515G>A NP_001393709.1:p.Val505= synonymous NM_001406781.1:c.1515G>A NP_001393710.1:p.Val505= synonymous NM_001406782.1:c.1515G>A NP_001393711.1:p.Val505= synonymous NM_001406783.1:c.1386G>A NP_001393712.1:p.Val462= synonymous NM_001406784.1:c.1422G>A NP_001393713.1:p.Val474= synonymous NM_001406785.1:c.1395G>A NP_001393714.1:p.Val465= synonymous NM_001406786.1:c.1386G>A NP_001393715.1:p.Val462= synonymous NM_001406787.1:c.1380G>A NP_001393716.1:p.Val460= synonymous NM_001406788.1:c.1227G>A NP_001393717.1:p.Val409= synonymous NM_001406789.1:c.1227G>A NP_001393718.1:p.Val409= synonymous NM_001406790.1:c.1227G>A NP_001393719.1:p.Val409= synonymous NM_001406791.1:c.1107G>A NP_001393720.1:p.Val369= synonymous NM_001406792.1:c.963G>A NP_001393721.1:p.Val321= synonymous NM_001406793.1:c.963G>A NP_001393722.1:p.Val321= synonymous NM_001406794.1:c.963G>A NP_001393723.1:p.Val321= synonymous NM_020629.2:c.2412G>A NP_065680.1:p.Val804= synonymous NM_020630.7:c.2412G>A NP_065681.1:p.Val804= synonymous NC_000010.11:g.43119550G>A NC_000010.10:g.43614998G>A NG_007489.1:g.47482G>A LRG_518:g.47482G>A LRG_518t1:c.2412G>A LRG_518p1:p.Val804= LRG_518t2:c.2412G>A LRG_518p2:p.Val804= - Protein change
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- Other names
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- Canonical SPDI
- NC_000010.11:43119549: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- 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 |
3595 | 3717 | |
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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Apr 29, 2022 | RCV001337765.6 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Nov 24, 2021 | RCV002255182.5 |
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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|---|---|---|---|---|---|
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Uncertain significance
(Nov 24, 2021)
|
criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002529976.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The RET c.2412G>A (p.V804=) variant has not been reported in the literature to our knowledge. It was observed in 2/119330 chromosomes of the Non-Finnish European … (more)
The RET c.2412G>A (p.V804=) variant has not been reported in the literature to our knowledge. It was observed in 2/119330 chromosomes of the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 1034965). Splice site prediction tools suggest the variant leads to the creation of a cryptic splice acceptor site, however these predictions have not been confirmed by transcriptional studies.The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
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Uncertain significance
(Apr 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001531380.4
First in ClinVar: Mar 22, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects codon 804 of the RET mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 804 of the RET mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RET protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 1034965). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
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Likely benign
(Apr 28, 2021)
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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: SCV002736158.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely 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)
|
Comment:
Comment:
This alteration is classified as likely 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.
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:
This sequence change affects codon 804 of the RET mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RET protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 1034965). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This alteration is classified as likely 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.
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 rs767045208 ...
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 Sep 29, 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.