This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1048 of the RET protein (p.Leu1048Val). This variant is present in population databases (rs774347808, gnomAD 0.003%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 22648184). ClinVar contains an entry for this variant (Variation ID: 372080). 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.3142C>G (p.Leu1048Val)
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.
(7)
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
7
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.3142C>G (p.Leu1048Val)
Variation ID: 372080 Accession: VCV000372080.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q11.21 10: 43126677 (GRCh38) [ NCBI UCSC ] 10: 43622125 (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 6, 2017 Jun 17, 2024 Jan 14, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.3142C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Leu1048Val missense NM_000323.2:c.3142C>G NP_000314.1:p.Leu1048Val missense NM_001355216.2:c.2380C>G NP_001342145.1:p.Leu794Val missense NM_001406743.1:c.3142C>G NP_001393672.1:p.Leu1048Val missense NM_001406744.1:c.3142C>G NP_001393673.1:p.Leu1048Val missense NM_001406761.1:c.3013C>G NP_001393690.1:p.Leu1005Val missense NM_001406762.1:c.3013C>G NP_001393691.1:p.Leu1005Val missense NM_001406763.1:c.3007C>G NP_001393692.1:p.Leu1003Val missense NM_001406764.1:c.3013C>G NP_001393693.1:p.Leu1005Val missense NM_001406765.1:c.3007C>G NP_001393694.1:p.Leu1003Val missense NM_001406766.1:c.2854C>G NP_001393695.1:p.Leu952Val missense NM_001406767.1:c.2854C>G NP_001393696.1:p.Leu952Val missense NM_001406768.1:c.2878C>G NP_001393697.1:p.Leu960Val missense NM_001406769.1:c.2746C>G NP_001393698.1:p.Leu916Val missense NM_001406770.1:c.2854C>G NP_001393699.1:p.Leu952Val missense NM_001406771.1:c.2704C>G NP_001393700.1:p.Leu902Val missense NM_001406772.1:c.2746C>G NP_001393701.1:p.Leu916Val missense NM_001406773.1:c.2704C>G NP_001393702.1:p.Leu902Val missense NM_001406774.1:c.2617C>G NP_001393703.1:p.Leu873Val missense NM_001406775.1:c.2416C>G NP_001393704.1:p.Leu806Val missense NM_001406776.1:c.2416C>G NP_001393705.1:p.Leu806Val missense NM_001406778.1:c.2416C>G NP_001393707.1:p.Leu806Val missense NM_001406779.1:c.2245C>G NP_001393708.1:p.Leu749Val missense NM_001406780.1:c.2245C>G NP_001393709.1:p.Leu749Val missense NM_001406781.1:c.2245C>G NP_001393710.1:p.Leu749Val missense NM_001406782.1:c.2245C>G NP_001393711.1:p.Leu749Val missense NM_001406783.1:c.2116C>G NP_001393712.1:p.Leu706Val missense NM_001406784.1:c.2152C>G NP_001393713.1:p.Leu718Val missense NM_001406785.1:c.2125C>G NP_001393714.1:p.Leu709Val missense NM_001406786.1:c.2116C>G NP_001393715.1:p.Leu706Val missense NM_001406787.1:c.2110C>G NP_001393716.1:p.Leu704Val missense NM_001406788.1:c.1957C>G NP_001393717.1:p.Leu653Val missense NM_001406789.1:c.1957C>G NP_001393718.1:p.Leu653Val missense NM_001406790.1:c.1957C>G NP_001393719.1:p.Leu653Val missense NM_001406791.1:c.1837C>G NP_001393720.1:p.Leu613Val missense NM_001406792.1:c.1693C>G NP_001393721.1:p.Leu565Val missense NM_001406794.1:c.1693C>G NP_001393723.1:p.Leu565Val missense NM_020629.2:c.3142C>G NP_065680.1:p.Leu1048Val missense NM_020630.7:c.3142C>G NP_065681.1:p.Leu1048Val missense NC_000010.11:g.43126677C>G NC_000010.10:g.43622125C>G NG_007489.1:g.54609C>G LRG_518:g.54609C>G LRG_518t1:c.3142C>G LRG_518p1:p.Leu1048Val LRG_518t2:c.3142C>G LRG_518p2:p.Leu1048Val - Protein change
- L1048V, L794V, L565V, L706V, L806V, L873V, L1005V, L613V, L653V, L704V, L749V, L902V, L1003V, L709V, L718V, L916V, L952V, L960V
- Other names
- -
- Canonical SPDI
- NC_000010.11:43126676:C:G
-
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.
-
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
|
Feb 12, 2016 | RCV000410987.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 12, 2016 | RCV000412050.3 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2023 | RCV000474558.13 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 28, 2022 | RCV000574881.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 13, 2022 | RCV003235199.1 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 14, 2024 | RCV004567898.1 |
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
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Feb 12, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2B
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489785.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Uncertain significance
(Feb 12, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489786.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Uncertain significance
(Oct 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543844.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1048 of the RET protein (p.Leu1048Val). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1048 of the RET protein (p.Leu1048Val). This variant is present in population databases (rs774347808, gnomAD 0.003%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 22648184). ClinVar contains an entry for this variant (Variation ID: 372080). 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)
|
|
|
Uncertain significance
(Oct 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000674751.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.L1048V variant (also known as c.3142C>G), located in coding exon 19 of the RET gene, results from a C to G substitution at nucleotide … (more)
The p.L1048V variant (also known as c.3142C>G), located in coding exon 19 of the RET gene, results from a C to G substitution at nucleotide position 3142. The leucine at codon 1048 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in an individual with Hirschsprung disease (Carter TC et al. J. Hum. Genet., 2012 Aug;57:485-93). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Dec 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003933570.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with Hirschprung disease (Carter et al., 2012); This variant is associated with the following publications: (PMID: 22648184, 14633923, 30034242, 29617658) (less)
|
|
|
Uncertain Significance
(Dec 01, 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: SCV004822638.1
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 leucine with valine at codon 1048 of the RET protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces leucine with valine at codon 1048 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related cancers in the literature. This variant has been identified in 5/251468 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: 5
|
|
|
Uncertain significance
(Jan 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005054209.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
Comment:
Comment:
The p.L1048V variant (also known as c.3142C>G), located in coding exon 19 of the RET gene, results from a C to G substitution at nucleotide position 3142. The leucine at codon 1048 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in an individual with Hirschsprung disease (Carter TC et al. J. Hum. Genet., 2012 Aug;57:485-93). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with Hirschprung disease (Carter et al., 2012); This variant is associated with the following publications: (PMID: 22648184, 14633923, 30034242, 29617658)
Comment:
This missense variant replaces leucine with valine at codon 1048 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related cancers in the literature. This variant has been identified in 5/251468 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:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1048 of the RET protein (p.Leu1048Val). This variant is present in population databases (rs774347808, gnomAD 0.003%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 22648184). ClinVar contains an entry for this variant (Variation ID: 372080). 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.L1048V variant (also known as c.3142C>G), located in coding exon 19 of the RET gene, results from a C to G substitution at nucleotide position 3142. The leucine at codon 1048 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in an individual with Hirschsprung disease (Carter TC et al. J. Hum. Genet., 2012 Aug;57:485-93). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with Hirschprung disease (Carter et al., 2012); This variant is associated with the following publications: (PMID: 22648184, 14633923, 30034242, 29617658)
Comment:
This missense variant replaces leucine with valine at codon 1048 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related cancers in the literature. This variant has been identified in 5/251468 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 |
|---|---|---|---|---|
| Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation. | Carter TC | Journal of human genetics | 2012 | PMID: 22648184 |
Text-mined citations for rs774347808 ...
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.