This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2531G>T (p.Arg844Leu)
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.
(5)
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
5
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.2531G>T (p.Arg844Leu)
Variation ID: 24952 Accession: VCV000024952.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43119669 (GRCh38) [ NCBI UCSC ] 10: 43615117 (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 Jan 6, 2017 May 1, 2024 Mar 14, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.2531G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Arg844Leu missense NM_000323.2:c.2531G>T NP_000314.1:p.Arg844Leu missense NM_001355216.2:c.1769G>T NP_001342145.1:p.Arg590Leu missense NM_001406743.1:c.2531G>T NP_001393672.1:p.Arg844Leu missense NM_001406744.1:c.2531G>T NP_001393673.1:p.Arg844Leu missense NM_001406759.1:c.2531G>T NP_001393688.1:p.Arg844Leu missense NM_001406760.1:c.2531G>T NP_001393689.1:p.Arg844Leu missense NM_001406761.1:c.2402G>T NP_001393690.1:p.Arg801Leu missense NM_001406762.1:c.2402G>T NP_001393691.1:p.Arg801Leu missense NM_001406763.1:c.2396G>T NP_001393692.1:p.Arg799Leu missense NM_001406764.1:c.2402G>T NP_001393693.1:p.Arg801Leu missense NM_001406765.1:c.2396G>T NP_001393694.1:p.Arg799Leu missense NM_001406766.1:c.2243G>T NP_001393695.1:p.Arg748Leu missense NM_001406767.1:c.2243G>T NP_001393696.1:p.Arg748Leu missense NM_001406768.1:c.2267G>T NP_001393697.1:p.Arg756Leu missense NM_001406769.1:c.2135G>T NP_001393698.1:p.Arg712Leu missense NM_001406770.1:c.2243G>T NP_001393699.1:p.Arg748Leu missense NM_001406771.1:c.2093G>T NP_001393700.1:p.Arg698Leu missense NM_001406772.1:c.2135G>T NP_001393701.1:p.Arg712Leu missense NM_001406773.1:c.2093G>T NP_001393702.1:p.Arg698Leu missense NM_001406774.1:c.2006G>T NP_001393703.1:p.Arg669Leu missense NM_001406775.1:c.1805G>T NP_001393704.1:p.Arg602Leu missense NM_001406776.1:c.1805G>T NP_001393705.1:p.Arg602Leu missense NM_001406777.1:c.1805G>T NP_001393706.1:p.Arg602Leu missense NM_001406778.1:c.1805G>T NP_001393707.1:p.Arg602Leu missense NM_001406779.1:c.1634G>T NP_001393708.1:p.Arg545Leu missense NM_001406780.1:c.1634G>T NP_001393709.1:p.Arg545Leu missense NM_001406781.1:c.1634G>T NP_001393710.1:p.Arg545Leu missense NM_001406782.1:c.1634G>T NP_001393711.1:p.Arg545Leu missense NM_001406783.1:c.1505G>T NP_001393712.1:p.Arg502Leu missense NM_001406784.1:c.1541G>T NP_001393713.1:p.Arg514Leu missense NM_001406785.1:c.1514G>T NP_001393714.1:p.Arg505Leu missense NM_001406786.1:c.1505G>T NP_001393715.1:p.Arg502Leu missense NM_001406787.1:c.1499G>T NP_001393716.1:p.Arg500Leu missense NM_001406788.1:c.1346G>T NP_001393717.1:p.Arg449Leu missense NM_001406789.1:c.1346G>T NP_001393718.1:p.Arg449Leu missense NM_001406790.1:c.1346G>T NP_001393719.1:p.Arg449Leu missense NM_001406791.1:c.1226G>T NP_001393720.1:p.Arg409Leu missense NM_001406792.1:c.1082G>T NP_001393721.1:p.Arg361Leu missense NM_001406793.1:c.1082G>T NP_001393722.1:p.Arg361Leu missense NM_001406794.1:c.1082G>T NP_001393723.1:p.Arg361Leu missense NM_020629.2:c.2531G>T NP_065680.1:p.Arg844Leu missense NM_020630.7:c.2531G>T NP_065681.1:p.Arg844Leu missense NC_000010.11:g.43119669G>T NC_000010.10:g.43615117G>T NG_007489.1:g.47601G>T LRG_518:g.47601G>T LRG_518t1:c.2531G>T LRG_518p1:p.Arg844Leu LRG_518t2:c.2531G>T LRG_518p2:p.Arg844Leu P07949:p.Arg844Leu - Protein change
- R844L, R590L, R502L, R514L, R669L, R698L, R799L, R801L, R409L, R449L, R748L, R500L, R602L, R712L, R756L, R361L, R505L, R545L
- Other names
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- Canonical SPDI
- NC_000010.11:43119668:G:T
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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. |
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| 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 (2) |
criteria provided, multiple submitters, no conflicts
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Apr 18, 2023 | RCV000410406.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Mar 15, 2023 | RCV000460812.18 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Sep 20, 2016 | RCV000409297.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Mar 14, 2024 | RCV002426514.9 |
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
(Sep 20, 2016)
|
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: SCV000490007.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Sep 20, 2016)
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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
|
Counsyl
Accession: SCV000490008.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Apr 18, 2023)
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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
|
Myriad Genetics, Inc.
Accession: SCV004018469.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Uncertain significance
(Mar 15, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543811.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 844 of the RET protein (p.Arg844Leu). … (more)
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 844 of the RET protein (p.Arg844Leu). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 24952). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 10826520, 28946813). This variant is present in population databases (rs55947360, gnomAD 0.002%). (less)
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Uncertain significance
(Mar 14, 2024)
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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: SCV002740537.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R844L variant (also known as c.2531G>T), located in coding exon 14 of the RET gene, results from a G to T substitution at nucleotide … (more)
The p.R844L variant (also known as c.2531G>T), located in coding exon 14 of the RET gene, results from a G to T substitution at nucleotide position 2531. The arginine at codon 844 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in individuals with familial medullary thyroid cancer; however, these individuals also carried another RET mutation, p.V804M (Bartsch DK et al. Exp Clin Endocrinol Diabetes 2000 ;108(2):128-32; Lebeault M et al. Thyroid 2017 12;27(12):1511-1522). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 844 of the RET protein (p.Arg844Leu). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 24952). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 10826520, 28946813). This variant is present in population databases (rs55947360, gnomAD 0.002%).
Comment:
The p.R844L variant (also known as c.2531G>T), located in coding exon 14 of the RET gene, results from a G to T substitution at nucleotide position 2531. The arginine at codon 844 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in individuals with familial medullary thyroid cancer; however, these individuals also carried another RET mutation, p.V804M (Bartsch DK et al. Exp Clin Endocrinol Diabetes 2000 ;108(2):128-32; Lebeault M et al. Thyroid 2017 12;27(12):1511-1522). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, 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 classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 844 of the RET protein (p.Arg844Leu). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 24952). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 10826520, 28946813). This variant is present in population databases (rs55947360, gnomAD 0.002%).
Comment:
The p.R844L variant (also known as c.2531G>T), located in coding exon 14 of the RET gene, results from a G to T substitution at nucleotide position 2531. The arginine at codon 844 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in individuals with familial medullary thyroid cancer; however, these individuals also carried another RET mutation, p.V804M (Bartsch DK et al. Exp Clin Endocrinol Diabetes 2000 ;108(2):128-32; Lebeault M et al. Thyroid 2017 12;27(12):1511-1522). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Nationwide French Study of RET Variants Detected from 2003 to 2013 Suggests a Possible Influence of Polymorphisms as Modifiers. | Lebeault M | Thyroid : official journal of the American Thyroid Association | 2017 | PMID: 28946813 |
| A RET double mutation in the germline of a kindred with FMTC. | Bartsch DK | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2000 | PMID: 10826520 |
Text-mined citations for rs55947360 ...
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 Nov 10, 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.