The c.45dupG pathogenic mutation, located in coding exon 1 of the RET gene, results from a duplication of G at nucleotide position 45, causing a translational frameshift with a predicted alternate stop codon (p.L16Afs*46). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in RET are known to cause Hirschsprung disease; however, such associations with Multiple Endocrine Neoplasia Type-2 (MEN2) have not been observed (Amiel J and Lyonnet S. J Med Genet. 2001 Nov;38(11):729-39; Wagner SM et al. Clinics (Sao Paulo). 2012;67 Suppl 1(Suppl 1):77-84). Based on the supporting evidence, this alteration is pathogenic for Hirschsprung disease; however, the association of this alteration with MEN2 is unlikely.
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.45dup (p.Leu16fs)
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.
(1)
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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.
Pathogenic
1
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.45dup (p.Leu16fs)
Variation ID: 1741794 Accession: VCV001741794.2
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43077302-43077303 (GRCh38) [ NCBI UCSC ] 10: 43572750-43572751 (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 Nov 29, 2022 May 1, 2024 Aug 31, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.45dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Leu16fs frameshift NM_000323.2:c.45dup NP_000314.1:p.Leu16Alafs frameshift NM_001406743.1:c.45dup NP_001393672.1:p.Leu16Alafs frameshift NM_001406744.1:c.45dup NP_001393673.1:p.Leu16Alafs frameshift NM_001406759.1:c.45dup NP_001393688.1:p.Leu16Alafs frameshift NM_001406760.1:c.45dup NP_001393689.1:p.Leu16Alafs frameshift NM_001406761.1:c.45dup NP_001393690.1:p.Leu16Alafs frameshift NM_001406762.1:c.45dup NP_001393691.1:p.Leu16Alafs frameshift NM_001406763.1:c.45dup NP_001393692.1:p.Leu16Alafs frameshift NM_001406764.1:c.45dup NP_001393693.1:p.Leu16Alafs frameshift NM_001406765.1:c.45dup NP_001393694.1:p.Leu16Alafs frameshift NM_001406766.1:c.45dup NP_001393695.1:p.Leu16Alafs frameshift NM_001406767.1:c.45dup NP_001393696.1:p.Leu16Alafs frameshift NM_001406768.1:c.45dup NP_001393697.1:p.Leu16Alafs frameshift NM_001406769.1:c.45dup NP_001393698.1:p.Leu16Alafs frameshift NM_001406770.1:c.45dup NP_001393699.1:p.Leu16Alafs frameshift NM_001406771.1:c.45dup NP_001393700.1:p.Leu16Alafs frameshift NM_001406772.1:c.45dup NP_001393701.1:p.Leu16Alafs frameshift NM_001406773.1:c.45dup NP_001393702.1:p.Leu16Alafs frameshift NM_001406774.1:c.45dup NP_001393703.1:p.Leu16Alafs frameshift NM_001406775.1:c.45dup NP_001393704.1:p.Leu16Alafs frameshift NM_001406776.1:c.45dup NP_001393705.1:p.Leu16Alafs frameshift NM_001406777.1:c.45dup NP_001393706.1:p.Leu16Alafs frameshift NM_001406778.1:c.45dup NP_001393707.1:p.Leu16Alafs frameshift NM_001406779.1:c.45dup NP_001393708.1:p.Leu16Alafs frameshift NM_001406780.1:c.45dup NP_001393709.1:p.Leu16Alafs frameshift NM_001406781.1:c.45dup NP_001393710.1:p.Leu16Alafs frameshift NM_001406782.1:c.45dup NP_001393711.1:p.Leu16Alafs frameshift NM_001406783.1:c.45dup NP_001393712.1:p.Leu16Alafs frameshift NM_001406784.1:c.45dup NP_001393713.1:p.Leu16Alafs frameshift NM_001406785.1:c.45dup NP_001393714.1:p.Leu16Alafs frameshift NM_001406786.1:c.45dup NP_001393715.1:p.Leu16Alafs frameshift NM_001406787.1:c.45dup NP_001393716.1:p.Leu16Alafs frameshift NM_001406788.1:c.45dup NP_001393717.1:p.Leu16Alafs frameshift NM_001406789.1:c.45dup NP_001393718.1:p.Leu16Alafs frameshift NM_001406790.1:c.45dup NP_001393719.1:p.Leu16Alafs frameshift NM_001406791.1:c.45dup NP_001393720.1:p.Leu16Alafs frameshift NM_001406792.1:c.45dup NP_001393721.1:p.Leu16Alafs frameshift NM_001406793.1:c.45dup NP_001393722.1:p.Leu16Alafs frameshift NM_001406794.1:c.45dup NP_001393723.1:p.Leu16Alafs frameshift NM_020629.2:c.45dup NP_065680.1:p.Leu16Alafs frameshift NM_020630.7:c.45dup NP_065681.1:p.Leu16Alafs frameshift NM_020975.4:c.45dupG frameshift NC_000010.11:g.43077303dup NC_000010.10:g.43572751dup NG_007489.1:g.5235dup NG_045003.1:g.4490dup LRG_518:g.5235dup LRG_518t1:c.45dup LRG_518p1:p.Leu16Alafs LRG_518t2:c.45dup LRG_518p2:p.Leu16Alafs - Protein change
- L16fs
- Other names
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- Canonical SPDI
- NC_000010.11:43077302:G:GG
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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. |
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| RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3598 | 3720 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
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Aug 31, 2022 | RCV002342361.2 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Aug 31, 2022)
|
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: SCV002637100.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.45dupG pathogenic mutation, located in coding exon 1 of the RET gene, results from a duplication of G at nucleotide position 45, causing a … (more)
The c.45dupG pathogenic mutation, located in coding exon 1 of the RET gene, results from a duplication of G at nucleotide position 45, causing a translational frameshift with a predicted alternate stop codon (p.L16Afs*46). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in RET are known to cause Hirschsprung disease; however, such associations with Multiple Endocrine Neoplasia Type-2 (MEN2) have not been observed (Amiel J and Lyonnet S. J Med Genet. 2001 Nov;38(11):729-39; Wagner SM et al. Clinics (Sao Paulo). 2012;67 Suppl 1(Suppl 1):77-84). Based on the supporting evidence, this alteration is pathogenic for Hirschsprung disease; however, the association of this alteration with MEN2 is unlikely. (less)
|
Comment:
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 c.45dupG pathogenic mutation, located in coding exon 1 of the RET gene, results from a duplication of G at nucleotide position 45, causing a translational frameshift with a predicted alternate stop codon (p.L16Afs*46). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in RET are known to cause Hirschsprung disease; however, such associations with Multiple Endocrine Neoplasia Type-2 (MEN2) have not been observed (Amiel J and Lyonnet S. J Med Genet. 2001 Nov;38(11):729-39; Wagner SM et al. Clinics (Sao Paulo). 2012;67 Suppl 1(Suppl 1):77-84). Based on the supporting evidence, this alteration is pathogenic for Hirschsprung disease; however, the association of this alteration with MEN2 is unlikely.
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 this variant ...
HelpRecord last updated May 01, 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.