This variant is also known as p.Ser147del. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with Hirschsprung disease (PMID: 24577265, 30693022). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.443_445del, results in the deletion of 1 amino acid(s) of the RET protein (p.Ser148del), but otherwise preserves the integrity of the reading frame.
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.443_445del (p.Ser148del)
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.
(5)
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
Likely pathogenic(1); Uncertain significance(3)
Likely pathogenic(1); Uncertain significance(3)
5
criteria provided, conflicting classifications
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.443_445del (p.Ser148del)
Variation ID: 2916120 Accession: VCV002916120.5
- Type and length
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Deletion, 3 bp
- Location
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Cytogenetic: 10q11.21 10: 43102445-43102447 (GRCh38) [ NCBI UCSC ] 10: 43597893-43597895 (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 Feb 20, 2024 Nov 10, 2024 May 1, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- S148del
- Other names
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- Canonical SPDI
- NC_000010.11:43102444:CTCCT:CT
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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 |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
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Jul 13, 2023 | RCV003647182.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Mar 12, 2024 | RCV004374328.1 | |
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RET-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jan 12, 2024 | RCV004539115.2 |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
May 1, 2024 | RCV004780639.1 |
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. |
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|---|---|---|---|---|---|
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Uncertain significance
(Jul 13, 2023)
|
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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004551262.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
This variant is also known as p.Ser147del. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, … (more)
This variant is also known as p.Ser147del. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with Hirschsprung disease (PMID: 24577265, 30693022). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.443_445del, results in the deletion of 1 amino acid(s) of the RET protein (p.Ser148del), but otherwise preserves the integrity of the reading frame. (less)
|
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Uncertain significance
(Mar 12, 2024)
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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: SCV005028313.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.443_445delCCT variant (also known as p.S148del) is located in coding exon 3 of the RET gene. This variant results from an in-frame CCT deletion … (more)
The c.443_445delCCT variant (also known as p.S148del) is located in coding exon 3 of the RET gene. This variant results from an in-frame CCT deletion at nucleotide positions 443 to 445. This results in the in-frame deletion of a serine at codon 148. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
|
|
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Likely pathogenic
(May 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV005389337.1
First in ClinVar: Nov 10, 2024 Last updated: Nov 10, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of one amino … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of one amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 24577265, 30693022, 37193168, 14633923) (less)
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Uncertain significance
(Sep 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
paternal
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Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV005393848.1
First in ClinVar: Nov 10, 2024 Last updated: Nov 10, 2024 |
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Uncertain significance
(Jan 12, 2024)
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no assertion criteria provided
Method: clinical testing
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RET-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004745668.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The RET c.443_445delCCT variant is predicted to result in an in-frame deletion (p.Ser148del). This variant has been reported in four affected individuals and one apparently … (more)
The RET c.443_445delCCT variant is predicted to result in an in-frame deletion (p.Ser148del). This variant has been reported in four affected individuals and one apparently unaffected individual in a family with Hirschsprung disease (Wu et al. 2018. PubMed ID: 30693022, as p.Phe147del) and was also reported in two related patients with Hirschsprung disease, who both inherited this variant from unaffected parents and one of these patients also carried DNMT3A variant (Torroglosa et al. 2014. PubMed ID: 24577265, as p.Ser147del) . This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
Comment:
Comment:
The c.443_445delCCT variant (also known as p.S148del) is located in coding exon 3 of the RET gene. This variant results from an in-frame CCT deletion at nucleotide positions 443 to 445. This results in the in-frame deletion of a serine at codon 148. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of one amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 24577265, 30693022, 37193168, 14633923)
Comment:
The RET c.443_445delCCT variant is predicted to result in an in-frame deletion (p.Ser148del). This variant has been reported in four affected individuals and one apparently unaffected individual in a family with Hirschsprung disease (Wu et al. 2018. PubMed ID: 30693022, as p.Phe147del) and was also reported in two related patients with Hirschsprung disease, who both inherited this variant from unaffected parents and one of these patients also carried DNMT3A variant (Torroglosa et al. 2014. PubMed ID: 24577265, as p.Ser147del) . This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, 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 variant is also known as p.Ser147del. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with Hirschsprung disease (PMID: 24577265, 30693022). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.443_445del, results in the deletion of 1 amino acid(s) of the RET protein (p.Ser148del), but otherwise preserves the integrity of the reading frame.
Comment:
The c.443_445delCCT variant (also known as p.S148del) is located in coding exon 3 of the RET gene. This variant results from an in-frame CCT deletion at nucleotide positions 443 to 445. This results in the in-frame deletion of a serine at codon 148. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of one amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 24577265, 30693022, 37193168, 14633923)
Comment:
The RET c.443_445delCCT variant is predicted to result in an in-frame deletion (p.Ser148del). This variant has been reported in four affected individuals and one apparently unaffected individual in a family with Hirschsprung disease (Wu et al. 2018. PubMed ID: 30693022, as p.Phe147del) and was also reported in two related patients with Hirschsprung disease, who both inherited this variant from unaffected parents and one of these patients also carried DNMT3A variant (Torroglosa et al. 2014. PubMed ID: 24577265, as p.Ser147del) . This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, 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| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole Exome Sequencing Identifies a Novel Pathogenic RET Variant in Hirschsprung Disease. | Wu W | Frontiers in genetics | 2019 | PMID: 30693022 |
| Involvement of DNMT3B in the pathogenesis of Hirschsprung disease and its possible role as a regulator of neurogenesis in the human enteric nervous system. | Torroglosa A | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24577265 |
Text-mined citations for this variant ...
HelpRecord 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.