This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 11 of the RET protein (p.Leu11Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 486316). 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.31C>A (p.Leu11Met)
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.
(6)
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.
Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(1); Likely benign(2)
Uncertain significance(2); Benign(1); Likely benign(2)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020975.6(RET):c.31C>A (p.Leu11Met)
Variation ID: 486316 Accession: VCV000486316.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43077289 (GRCh38) [ NCBI UCSC ] 10: 43572737 (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 Jan 1, 2018 Oct 8, 2024 Jan 18, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.31C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Leu11Met missense NM_000323.2:c.31C>A NP_000314.1:p.Leu11Met missense NM_001406743.1:c.31C>A NP_001393672.1:p.Leu11Met missense NM_001406744.1:c.31C>A NP_001393673.1:p.Leu11Met missense NM_001406759.1:c.31C>A NP_001393688.1:p.Leu11Met missense NM_001406760.1:c.31C>A NP_001393689.1:p.Leu11Met missense NM_001406761.1:c.31C>A NP_001393690.1:p.Leu11Met missense NM_001406762.1:c.31C>A NP_001393691.1:p.Leu11Met missense NM_001406763.1:c.31C>A NP_001393692.1:p.Leu11Met missense NM_001406764.1:c.31C>A NP_001393693.1:p.Leu11Met missense NM_001406765.1:c.31C>A NP_001393694.1:p.Leu11Met missense NM_001406766.1:c.31C>A NP_001393695.1:p.Leu11Met missense NM_001406767.1:c.31C>A NP_001393696.1:p.Leu11Met missense NM_001406768.1:c.31C>A NP_001393697.1:p.Leu11Met missense NM_001406769.1:c.31C>A NP_001393698.1:p.Leu11Met missense NM_001406770.1:c.31C>A NP_001393699.1:p.Leu11Met missense NM_001406771.1:c.31C>A NP_001393700.1:p.Leu11Met missense NM_001406772.1:c.31C>A NP_001393701.1:p.Leu11Met missense NM_001406773.1:c.31C>A NP_001393702.1:p.Leu11Met missense NM_001406774.1:c.31C>A NP_001393703.1:p.Leu11Met missense NM_001406775.1:c.31C>A NP_001393704.1:p.Leu11Met missense NM_001406776.1:c.31C>A NP_001393705.1:p.Leu11Met missense NM_001406777.1:c.31C>A NP_001393706.1:p.Leu11Met missense NM_001406778.1:c.31C>A NP_001393707.1:p.Leu11Met missense NM_001406779.1:c.31C>A NP_001393708.1:p.Leu11Met missense NM_001406780.1:c.31C>A NP_001393709.1:p.Leu11Met missense NM_001406781.1:c.31C>A NP_001393710.1:p.Leu11Met missense NM_001406782.1:c.31C>A NP_001393711.1:p.Leu11Met missense NM_001406783.1:c.31C>A NP_001393712.1:p.Leu11Met missense NM_001406784.1:c.31C>A NP_001393713.1:p.Leu11Met missense NM_001406785.1:c.31C>A NP_001393714.1:p.Leu11Met missense NM_001406786.1:c.31C>A NP_001393715.1:p.Leu11Met missense NM_001406787.1:c.31C>A NP_001393716.1:p.Leu11Met missense NM_001406788.1:c.31C>A NP_001393717.1:p.Leu11Met missense NM_001406789.1:c.31C>A NP_001393718.1:p.Leu11Met missense NM_001406790.1:c.31C>A NP_001393719.1:p.Leu11Met missense NM_001406791.1:c.31C>A NP_001393720.1:p.Leu11Met missense NM_001406792.1:c.31C>A NP_001393721.1:p.Leu11Met missense NM_001406793.1:c.31C>A NP_001393722.1:p.Leu11Met missense NM_001406794.1:c.31C>A NP_001393723.1:p.Leu11Met missense NM_020629.2:c.31C>A NP_065680.1:p.Leu11Met missense NM_020630.7:c.31C>A NP_065681.1:p.Leu11Met missense NC_000010.11:g.43077289C>A NC_000010.10:g.43572737C>A NG_007489.1:g.5221C>A NG_045003.1:g.4476C>A LRG_518:g.5221C>A LRG_518t1:c.31C>A LRG_518p1:p.Leu11Met LRG_518t2:c.31C>A LRG_518p2:p.Leu11Met - Protein change
- L11M
- Other names
- -
- Canonical SPDI
- NC_000010.11:43077288:C:A
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00023
- 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 |
3598 | 3720 | |
| 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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jul 26, 2023 | RCV000575741.7 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jan 18, 2024 | RCV000689589.11 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 24, 2018 | RCV001821691.4 | |
|
RET-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Jul 11, 2024 | RCV004530620.2 |
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. |
|
|---|---|---|---|---|---|
|
Likely benign
(Apr 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002068971.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
|
Uncertain significance
(Nov 15, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002527907.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The RET c.31C>A (p.L11M) variant has not been reported in the literature to our knowledge. It was observed in 13/11598 chromosomes of the African/African American … (more)
The RET c.31C>A (p.L11M) variant has not been reported in the literature to our knowledge. It was observed in 13/11598 chromosomes of the African/African American subpopulation, according to Genome Aggregation Database (http://gnomad.broadinstitute.org). The variant has been reported in ClinVar (Variation ID 486316). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Uncertain significance
(Jan 18, 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: SCV000817246.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 11 of the RET protein (p.Leu11Met). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 11 of the RET protein (p.Leu11Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 486316). 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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Likely Benign
(Dec 18, 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: SCV004838618.1
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)
|
Number of individuals with the variant: 10
|
|
|
Benign
(Jul 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000674837.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Uncertain significance
(Jul 11, 2024)
|
no assertion criteria provided
Method: clinical testing
|
RET-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004739289.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The RET c.31C>A variant is predicted to result in the amino acid substitution p.Leu11Met. To our knowledge, this variant has not been reported in the … (more)
The RET c.31C>A variant is predicted to result in the amino acid substitution p.Leu11Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/486316/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
Comment:
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
The RET c.31C>A variant is predicted to result in the amino acid substitution p.Leu11Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/486316/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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 leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 11 of the RET protein (p.Leu11Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 486316). 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:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
The RET c.31C>A variant is predicted to result in the amino acid substitution p.Leu11Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/486316/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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 rs587780812 ...
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 25, 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.