ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2182A>G (p.Lys728Glu)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.2182A>G (p.Lys728Glu)
Variation ID: 570574 Accession: VCV000570574.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43116629 (GRCh38) [ NCBI UCSC ] 10: 43612077 (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 Oct 10, 2018 Feb 20, 2024 Jun 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.2182A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Lys728Glu missense NM_000323.2:c.2182A>G NP_000314.1:p.Lys728Glu missense NM_001355216.2:c.1420A>G NP_001342145.1:p.Lys474Glu missense NM_001406743.1:c.2182A>G NP_001393672.1:p.Lys728Glu missense NM_001406744.1:c.2182A>G NP_001393673.1:p.Lys728Glu missense NM_001406759.1:c.2182A>G NP_001393688.1:p.Lys728Glu missense NM_001406760.1:c.2182A>G NP_001393689.1:p.Lys728Glu missense NM_001406761.1:c.2053A>G NP_001393690.1:p.Lys685Glu missense NM_001406762.1:c.2053A>G NP_001393691.1:p.Lys685Glu missense NM_001406763.1:c.2047A>G NP_001393692.1:p.Lys683Glu missense NM_001406764.1:c.2053A>G NP_001393693.1:p.Lys685Glu missense NM_001406765.1:c.2047A>G NP_001393694.1:p.Lys683Glu missense NM_001406766.1:c.1894A>G NP_001393695.1:p.Lys632Glu missense NM_001406767.1:c.1894A>G NP_001393696.1:p.Lys632Glu missense NM_001406768.1:c.1918A>G NP_001393697.1:p.Lys640Glu missense NM_001406769.1:c.1786A>G NP_001393698.1:p.Lys596Glu missense NM_001406770.1:c.1894A>G NP_001393699.1:p.Lys632Glu missense NM_001406771.1:c.1744A>G NP_001393700.1:p.Lys582Glu missense NM_001406772.1:c.1786A>G NP_001393701.1:p.Lys596Glu missense NM_001406773.1:c.1744A>G NP_001393702.1:p.Lys582Glu missense NM_001406774.1:c.1657A>G NP_001393703.1:p.Lys553Glu missense NM_001406775.1:c.1456A>G NP_001393704.1:p.Lys486Glu missense NM_001406776.1:c.1456A>G NP_001393705.1:p.Lys486Glu missense NM_001406777.1:c.1456A>G NP_001393706.1:p.Lys486Glu missense NM_001406778.1:c.1456A>G NP_001393707.1:p.Lys486Glu missense NM_001406779.1:c.1285A>G NP_001393708.1:p.Lys429Glu missense NM_001406780.1:c.1285A>G NP_001393709.1:p.Lys429Glu missense NM_001406781.1:c.1285A>G NP_001393710.1:p.Lys429Glu missense NM_001406782.1:c.1285A>G NP_001393711.1:p.Lys429Glu missense NM_001406783.1:c.1156A>G NP_001393712.1:p.Lys386Glu missense NM_001406784.1:c.1192A>G NP_001393713.1:p.Lys398Glu missense NM_001406785.1:c.1165A>G NP_001393714.1:p.Lys389Glu missense NM_001406786.1:c.1156A>G NP_001393715.1:p.Lys386Glu missense NM_001406787.1:c.1150A>G NP_001393716.1:p.Lys384Glu missense NM_001406788.1:c.997A>G NP_001393717.1:p.Lys333Glu missense NM_001406789.1:c.997A>G NP_001393718.1:p.Lys333Glu missense NM_001406790.1:c.997A>G NP_001393719.1:p.Lys333Glu missense NM_001406791.1:c.877A>G NP_001393720.1:p.Lys293Glu missense NM_001406792.1:c.733A>G NP_001393721.1:p.Lys245Glu missense NM_001406793.1:c.733A>G NP_001393722.1:p.Lys245Glu missense NM_001406794.1:c.733A>G NP_001393723.1:p.Lys245Glu missense NM_020629.2:c.2182A>G NP_065680.1:p.Lys728Glu missense NM_020630.7:c.2182A>G NP_065681.1:p.Lys728Glu missense NC_000010.11:g.43116629A>G NC_000010.10:g.43612077A>G NG_007489.1:g.44561A>G LRG_518:g.44561A>G LRG_518t1:c.2182A>G LRG_518p1:p.Lys728Glu LRG_518t2:c.2182A>G LRG_518p2:p.Lys728Glu - Protein change
- K728E, K474E, K245E, K389E, K553E, K333E, K632E, K293E, K386E, K429E, K486E, K582E, K596E, K640E, K384E, K398E, K683E, K685E
- Other names
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- Canonical SPDI
- NC_000010.11:43116628: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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 |
3382 | 3500 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Jun 21, 2023 | RCV000691463.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 5, 2021 | RCV002424623.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 10, 2022 | RCV002485646.1 |
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
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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
(Jun 21, 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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Invitae
Accession: SCV000819242.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
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. … (more)
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. ClinVar contains an entry for this variant (Variation ID: 570574). This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is present in population databases (rs147216744, gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 728 of the RET protein (p.Lys728Glu). (less)
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Uncertain significance
(Jan 05, 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: SCV002728520.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.K728E variant (also known as c.2182A>G), located in coding exon 12 of the RET gene, results from an A to G substitution at nucleotide … (more)
The p.K728E variant (also known as c.2182A>G), located in coding exon 12 of the RET gene, results from an A to G substitution at nucleotide position 2182. The lysine at codon 728 is replaced by glutamic acid, 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 deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jan 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 1
Familial medullary thyroid carcinoma Multiple endocrine neoplasia, type 2b Pheochromocytoma Multiple endocrine neoplasia, type 2a
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002783807.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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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. |
Citations for germline classification of this variant
HelpThere 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 rs147216744 ...
HelpRecord last updated Feb 28, 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.