The p.K821E variant (also known as c.2461A>G), located in coding exon 14 of the RET gene, results from an A to G substitution at nucleotide position 2461. The lysine at codon 821 is replaced by glutamic acid, an amino acid with similar properties. This variant was identified in one family from a MEN2 testing cohort (Elisei R et al. Genes (Basel), 2019 09;10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2461A>G (p.Lys821Glu)
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.
Uncertain significance
3
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.2461A>G (p.Lys821Glu)
Variation ID: 229991 Accession: VCV000229991.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43119599 (GRCh38) [ NCBI UCSC ] 10: 43615047 (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 May 29, 2016 May 1, 2024 Jan 16, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.2461A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Lys821Glu missense NM_000323.2:c.2461A>G NP_000314.1:p.Lys821Glu missense NM_001355216.2:c.1699A>G NP_001342145.1:p.Lys567Glu missense NM_001406743.1:c.2461A>G NP_001393672.1:p.Lys821Glu missense NM_001406744.1:c.2461A>G NP_001393673.1:p.Lys821Glu missense NM_001406759.1:c.2461A>G NP_001393688.1:p.Lys821Glu missense NM_001406760.1:c.2461A>G NP_001393689.1:p.Lys821Glu missense NM_001406761.1:c.2332A>G NP_001393690.1:p.Lys778Glu missense NM_001406762.1:c.2332A>G NP_001393691.1:p.Lys778Glu missense NM_001406763.1:c.2326A>G NP_001393692.1:p.Lys776Glu missense NM_001406764.1:c.2332A>G NP_001393693.1:p.Lys778Glu missense NM_001406765.1:c.2326A>G NP_001393694.1:p.Lys776Glu missense NM_001406766.1:c.2173A>G NP_001393695.1:p.Lys725Glu missense NM_001406767.1:c.2173A>G NP_001393696.1:p.Lys725Glu missense NM_001406768.1:c.2197A>G NP_001393697.1:p.Lys733Glu missense NM_001406769.1:c.2065A>G NP_001393698.1:p.Lys689Glu missense NM_001406770.1:c.2173A>G NP_001393699.1:p.Lys725Glu missense NM_001406771.1:c.2023A>G NP_001393700.1:p.Lys675Glu missense NM_001406772.1:c.2065A>G NP_001393701.1:p.Lys689Glu missense NM_001406773.1:c.2023A>G NP_001393702.1:p.Lys675Glu missense NM_001406774.1:c.1936A>G NP_001393703.1:p.Lys646Glu missense NM_001406775.1:c.1735A>G NP_001393704.1:p.Lys579Glu missense NM_001406776.1:c.1735A>G NP_001393705.1:p.Lys579Glu missense NM_001406777.1:c.1735A>G NP_001393706.1:p.Lys579Glu missense NM_001406778.1:c.1735A>G NP_001393707.1:p.Lys579Glu missense NM_001406779.1:c.1564A>G NP_001393708.1:p.Lys522Glu missense NM_001406780.1:c.1564A>G NP_001393709.1:p.Lys522Glu missense NM_001406781.1:c.1564A>G NP_001393710.1:p.Lys522Glu missense NM_001406782.1:c.1564A>G NP_001393711.1:p.Lys522Glu missense NM_001406783.1:c.1435A>G NP_001393712.1:p.Lys479Glu missense NM_001406784.1:c.1471A>G NP_001393713.1:p.Lys491Glu missense NM_001406785.1:c.1444A>G NP_001393714.1:p.Lys482Glu missense NM_001406786.1:c.1435A>G NP_001393715.1:p.Lys479Glu missense NM_001406787.1:c.1429A>G NP_001393716.1:p.Lys477Glu missense NM_001406788.1:c.1276A>G NP_001393717.1:p.Lys426Glu missense NM_001406789.1:c.1276A>G NP_001393718.1:p.Lys426Glu missense NM_001406790.1:c.1276A>G NP_001393719.1:p.Lys426Glu missense NM_001406791.1:c.1156A>G NP_001393720.1:p.Lys386Glu missense NM_001406792.1:c.1012A>G NP_001393721.1:p.Lys338Glu missense NM_001406793.1:c.1012A>G NP_001393722.1:p.Lys338Glu missense NM_001406794.1:c.1012A>G NP_001393723.1:p.Lys338Glu missense NM_020629.2:c.2461A>G NP_065680.1:p.Lys821Glu missense NM_020630.7:c.2461A>G NP_065681.1:p.Lys821Glu missense NC_000010.11:g.43119599A>G NC_000010.10:g.43615047A>G NG_007489.1:g.47531A>G LRG_518:g.47531A>G LRG_518t1:c.2461A>G LRG_518p1:p.Lys821Glu LRG_518t2:c.2461A>G LRG_518p2:p.Lys821Glu - Protein change
- K821E, K567E, K338E, K477E, K482E, K522E, K579E, K426E, K675E, K725E, K733E, K776E, K386E, K479E, K491E, K778E, K646E, K689E
- Other names
- -
- Canonical SPDI
- NC_000010.11:43119598:A: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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The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 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
|
Jul 13, 2023 | RCV000220695.5 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 16, 2024 | RCV000692117.11 |
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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|---|---|---|---|---|---|
|
Uncertain significance
(Jul 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000273388.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.K821E variant (also known as c.2461A>G), located in coding exon 14 of the RET gene, results from an A to G substitution at nucleotide … (more)
The p.K821E variant (also known as c.2461A>G), located in coding exon 14 of the RET gene, results from an A to G substitution at nucleotide position 2461. The lysine at codon 821 is replaced by glutamic acid, an amino acid with similar properties. This variant was identified in one family from a MEN2 testing cohort (Elisei R et al. Genes (Basel), 2019 09;10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000819925.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 821 of the RET protein … (more)
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 821 of the RET protein (p.Lys821Glu). This variant is present in population databases (rs749421642, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Hirschsprung’s disease (PMID: 31510104). ClinVar contains an entry for this variant (Variation ID: 229991). 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. 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)
|
|
|
Uncertain Significance
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004838673.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces lysine with glutamic acid at codon 821 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant … (more)
This missense variant replaces lysine with glutamic acid at codon 821 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/248002 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
|
Comment:
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 821 of the RET protein (p.Lys821Glu). This variant is present in population databases (rs749421642, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Hirschsprung’s disease (PMID: 31510104). ClinVar contains an entry for this variant (Variation ID: 229991). 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. 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 missense variant replaces lysine with glutamic acid at codon 821 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/248002 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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 p.K821E variant (also known as c.2461A>G), located in coding exon 14 of the RET gene, results from an A to G substitution at nucleotide position 2461. The lysine at codon 821 is replaced by glutamic acid, an amino acid with similar properties. This variant was identified in one family from a MEN2 testing cohort (Elisei R et al. Genes (Basel), 2019 09;10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 821 of the RET protein (p.Lys821Glu). This variant is present in population databases (rs749421642, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Hirschsprung’s disease (PMID: 31510104). ClinVar contains an entry for this variant (Variation ID: 229991). 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. 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 missense variant replaces lysine with glutamic acid at codon 821 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/248002 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations. | Elisei R | Genes | 2019 | PMID: 31510104 |
Text-mined citations for rs749421642 ...
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.