This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 3 of the RET protein (p.Lys3Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RET-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 584566). 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 tolerated. 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.7A>G (p.Lys3Glu)
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.
(4)
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
4
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.7A>G (p.Lys3Glu)
Variation ID: 584566 Accession: VCV000584566.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43077265 (GRCh38) [ NCBI UCSC ] 10: 43572713 (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 Aug 11, 2024 Jun 13, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.7A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Lys3Glu missense NM_000323.2:c.7A>G NP_000314.1:p.Lys3Glu missense NM_001406743.1:c.7A>G NP_001393672.1:p.Lys3Glu missense NM_001406744.1:c.7A>G NP_001393673.1:p.Lys3Glu missense NM_001406759.1:c.7A>G NP_001393688.1:p.Lys3Glu missense NM_001406760.1:c.7A>G NP_001393689.1:p.Lys3Glu missense NM_001406761.1:c.7A>G NP_001393690.1:p.Lys3Glu missense NM_001406762.1:c.7A>G NP_001393691.1:p.Lys3Glu missense NM_001406763.1:c.7A>G NP_001393692.1:p.Lys3Glu missense NM_001406764.1:c.7A>G NP_001393693.1:p.Lys3Glu missense NM_001406765.1:c.7A>G NP_001393694.1:p.Lys3Glu missense NM_001406766.1:c.7A>G NP_001393695.1:p.Lys3Glu missense NM_001406767.1:c.7A>G NP_001393696.1:p.Lys3Glu missense NM_001406768.1:c.7A>G NP_001393697.1:p.Lys3Glu missense NM_001406769.1:c.7A>G NP_001393698.1:p.Lys3Glu missense NM_001406770.1:c.7A>G NP_001393699.1:p.Lys3Glu missense NM_001406771.1:c.7A>G NP_001393700.1:p.Lys3Glu missense NM_001406772.1:c.7A>G NP_001393701.1:p.Lys3Glu missense NM_001406773.1:c.7A>G NP_001393702.1:p.Lys3Glu missense NM_001406774.1:c.7A>G NP_001393703.1:p.Lys3Glu missense NM_001406775.1:c.7A>G NP_001393704.1:p.Lys3Glu missense NM_001406776.1:c.7A>G NP_001393705.1:p.Lys3Glu missense NM_001406777.1:c.7A>G NP_001393706.1:p.Lys3Glu missense NM_001406778.1:c.7A>G NP_001393707.1:p.Lys3Glu missense NM_001406779.1:c.7A>G NP_001393708.1:p.Lys3Glu missense NM_001406780.1:c.7A>G NP_001393709.1:p.Lys3Glu missense NM_001406781.1:c.7A>G NP_001393710.1:p.Lys3Glu missense NM_001406782.1:c.7A>G NP_001393711.1:p.Lys3Glu missense NM_001406783.1:c.7A>G NP_001393712.1:p.Lys3Glu missense NM_001406784.1:c.7A>G NP_001393713.1:p.Lys3Glu missense NM_001406785.1:c.7A>G NP_001393714.1:p.Lys3Glu missense NM_001406786.1:c.7A>G NP_001393715.1:p.Lys3Glu missense NM_001406787.1:c.7A>G NP_001393716.1:p.Lys3Glu missense NM_001406788.1:c.7A>G NP_001393717.1:p.Lys3Glu missense NM_001406789.1:c.7A>G NP_001393718.1:p.Lys3Glu missense NM_001406790.1:c.7A>G NP_001393719.1:p.Lys3Glu missense NM_001406791.1:c.7A>G NP_001393720.1:p.Lys3Glu missense NM_001406792.1:c.7A>G NP_001393721.1:p.Lys3Glu missense NM_001406793.1:c.7A>G NP_001393722.1:p.Lys3Glu missense NM_001406794.1:c.7A>G NP_001393723.1:p.Lys3Glu missense NM_020629.2:c.7A>G NP_065680.1:p.Lys3Glu missense NM_020630.7:c.7A>G NP_065681.1:p.Lys3Glu missense NC_000010.11:g.43077265A>G NC_000010.10:g.43572713A>G NG_007489.1:g.5197A>G NG_045003.1:g.4452A>G LRG_518:g.5197A>G LRG_518t1:c.7A>G LRG_518p1:p.Lys3Glu LRG_518t2:c.7A>G LRG_518p2:p.Lys3Glu - Protein change
- K3E
- Other names
- -
- Canonical SPDI
- NC_000010.11:43077264: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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- 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 |
3599 | 3721 | |
| LOC106736614 | - | - | - | GRCh38 | - | 75 |
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
|
Jun 13, 2024 | RCV000708761.5 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 16, 2023 | RCV001213441.12 |
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
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000822201.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
|
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Uncertain significance
(Dec 16, 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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001385071.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 3 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 3 of the RET protein (p.Lys3Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RET-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 584566). 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 tolerated. 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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Uncertain Significance
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004828158.1
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)
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Number of individuals with the variant: 1
Zygosity: Single Heterozygote
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|
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Uncertain significance
(Jun 13, 2024)
|
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: SCV002678625.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The p.K3E variant (also known as c.7A>G), located in coding exon 1 of the RET gene, results from an A to G substitution at nucleotide … (more)
The p.K3E variant (also known as c.7A>G), located in coding exon 1 of the RET gene, results from an A to G substitution at nucleotide position 7. The lysine at codon 3 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported as variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. (less)
|
Comment:
Comment:
The p.K3E variant (also known as c.7A>G), located in coding exon 1 of the RET gene, results from an A to G substitution at nucleotide position 7. The lysine at codon 3 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported as variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant 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 sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 3 of the RET protein (p.Lys3Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RET-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 584566). 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 tolerated. 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:
The p.K3E variant (also known as c.7A>G), located in coding exon 1 of the RET gene, results from an A to G substitution at nucleotide position 7. The lysine at codon 3 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported as variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Text-mined citations for rs1564480827 ...
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.