This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with RET-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 845 of the RET protein (p.Ala845Val).
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2534C>T (p.Ala845Val)
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
-
NM_020975.6(RET):c.2534C>T (p.Ala845Val)
Variation ID: 2140620 Accession: VCV002140620.4
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q11.21 10: 43119672 (GRCh38) [ NCBI UCSC ] 10: 43615120 (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 Feb 8, 2023 May 1, 2024 May 4, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.2534C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Ala845Val missense NM_000323.2:c.2534C>T NP_000314.1:p.Ala845Val missense NM_001355216.2:c.1772C>T NP_001342145.1:p.Ala591Val missense NM_001406743.1:c.2534C>T NP_001393672.1:p.Ala845Val missense NM_001406744.1:c.2534C>T NP_001393673.1:p.Ala845Val missense NM_001406759.1:c.2534C>T NP_001393688.1:p.Ala845Val missense NM_001406760.1:c.2534C>T NP_001393689.1:p.Ala845Val missense NM_001406761.1:c.2405C>T NP_001393690.1:p.Ala802Val missense NM_001406762.1:c.2405C>T NP_001393691.1:p.Ala802Val missense NM_001406763.1:c.2399C>T NP_001393692.1:p.Ala800Val missense NM_001406764.1:c.2405C>T NP_001393693.1:p.Ala802Val missense NM_001406765.1:c.2399C>T NP_001393694.1:p.Ala800Val missense NM_001406766.1:c.2246C>T NP_001393695.1:p.Ala749Val missense NM_001406767.1:c.2246C>T NP_001393696.1:p.Ala749Val missense NM_001406768.1:c.2270C>T NP_001393697.1:p.Ala757Val missense NM_001406769.1:c.2138C>T NP_001393698.1:p.Ala713Val missense NM_001406770.1:c.2246C>T NP_001393699.1:p.Ala749Val missense NM_001406771.1:c.2096C>T NP_001393700.1:p.Ala699Val missense NM_001406772.1:c.2138C>T NP_001393701.1:p.Ala713Val missense NM_001406773.1:c.2096C>T NP_001393702.1:p.Ala699Val missense NM_001406774.1:c.2009C>T NP_001393703.1:p.Ala670Val missense NM_001406775.1:c.1808C>T NP_001393704.1:p.Ala603Val missense NM_001406776.1:c.1808C>T NP_001393705.1:p.Ala603Val missense NM_001406777.1:c.1808C>T NP_001393706.1:p.Ala603Val missense NM_001406778.1:c.1808C>T NP_001393707.1:p.Ala603Val missense NM_001406779.1:c.1637C>T NP_001393708.1:p.Ala546Val missense NM_001406780.1:c.1637C>T NP_001393709.1:p.Ala546Val missense NM_001406781.1:c.1637C>T NP_001393710.1:p.Ala546Val missense NM_001406782.1:c.1637C>T NP_001393711.1:p.Ala546Val missense NM_001406783.1:c.1508C>T NP_001393712.1:p.Ala503Val missense NM_001406784.1:c.1544C>T NP_001393713.1:p.Ala515Val missense NM_001406785.1:c.1517C>T NP_001393714.1:p.Ala506Val missense NM_001406786.1:c.1508C>T NP_001393715.1:p.Ala503Val missense NM_001406787.1:c.1502C>T NP_001393716.1:p.Ala501Val missense NM_001406788.1:c.1349C>T NP_001393717.1:p.Ala450Val missense NM_001406789.1:c.1349C>T NP_001393718.1:p.Ala450Val missense NM_001406790.1:c.1349C>T NP_001393719.1:p.Ala450Val missense NM_001406791.1:c.1229C>T NP_001393720.1:p.Ala410Val missense NM_001406792.1:c.1085C>T NP_001393721.1:p.Ala362Val missense NM_001406793.1:c.1085C>T NP_001393722.1:p.Ala362Val missense NM_001406794.1:c.1085C>T NP_001393723.1:p.Ala362Val missense NM_020629.2:c.2534C>T NP_065680.1:p.Ala845Val missense NM_020630.7:c.2534C>T NP_065681.1:p.Ala845Val missense NC_000010.11:g.43119672C>T NC_000010.10:g.43615120C>T NG_007489.1:g.47604C>T LRG_518:g.47604C>T LRG_518t1:c.2534C>T LRG_518p1:p.Ala845Val LRG_518t2:c.2534C>T LRG_518p2:p.Ala845Val - Protein change
- A362V, A591V, A749V, A800V, A501V, A503V, A699V, A757V, A802V, A515V, A546V, A603V, A410V, A450V, A506V, A670V, A713V, A845V
- Other names
- -
- Canonical SPDI
- NC_000010.11:43119671: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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
|
Oct 9, 2022 | RCV003056542.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 4, 2023 | RCV003274180.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Oct 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003448026.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this … (more)
This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with RET-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 845 of the RET protein (p.Ala845Val). (less)
|
|
|
Uncertain significance
(May 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004009449.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The p.A845V variant (also known as c.2534C>T), located in coding exon 14 of the RET gene, results from a C to T substitution at nucleotide … (more)
The p.A845V variant (also known as c.2534C>T), located in coding exon 14 of the RET gene, results from a C to T substitution at nucleotide position 2534. The alanine at codon 845 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
Comment:
Comment:
The p.A845V variant (also known as c.2534C>T), located in coding exon 14 of the RET gene, results from a C to T substitution at nucleotide position 2534. The alanine at codon 845 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with RET-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 845 of the RET protein (p.Ala845Val).
Comment:
The p.A845V variant (also known as c.2534C>T), located in coding exon 14 of the RET gene, results from a C to T substitution at nucleotide position 2534. The alanine at codon 845 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 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.