ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.1423C>T (p.Arg475Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.1423C>T (p.Arg475Trp)
Variation ID: 572175 Accession: VCV000572175.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43111366 (GRCh38) [ NCBI UCSC ] 10: 43606814 (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 Apr 20, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.1423C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Arg475Trp missense NM_000323.2:c.1423C>T NP_000314.1:p.Arg475Trp missense NM_001355216.2:c.661C>T NP_001342145.1:p.Arg221Trp missense NM_001406743.1:c.1423C>T NP_001393672.1:p.Arg475Trp missense NM_001406744.1:c.1423C>T NP_001393673.1:p.Arg475Trp missense NM_001406759.1:c.1423C>T NP_001393688.1:p.Arg475Trp missense NM_001406760.1:c.1423C>T NP_001393689.1:p.Arg475Trp missense NM_001406761.1:c.1294C>T NP_001393690.1:p.Arg432Trp missense NM_001406762.1:c.1294C>T NP_001393691.1:p.Arg432Trp missense NM_001406763.1:c.1423C>T NP_001393692.1:p.Arg475Trp missense NM_001406764.1:c.1294C>T NP_001393693.1:p.Arg432Trp missense NM_001406765.1:c.1423C>T NP_001393694.1:p.Arg475Trp missense NM_001406766.1:c.1135C>T NP_001393695.1:p.Arg379Trp missense NM_001406767.1:c.1135C>T NP_001393696.1:p.Arg379Trp missense NM_001406768.1:c.1294C>T NP_001393697.1:p.Arg432Trp missense NM_001406769.1:c.1027C>T NP_001393698.1:p.Arg343Trp missense NM_001406770.1:c.1135C>T NP_001393699.1:p.Arg379Trp missense NM_001406771.1:c.985C>T NP_001393700.1:p.Arg329Trp missense NM_001406772.1:c.1027C>T NP_001393701.1:p.Arg343Trp missense NM_001406773.1:c.985C>T NP_001393702.1:p.Arg329Trp missense NM_001406774.1:c.898C>T NP_001393703.1:p.Arg300Trp missense NM_001406775.1:c.697C>T NP_001393704.1:p.Arg233Trp missense NM_001406776.1:c.697C>T NP_001393705.1:p.Arg233Trp missense NM_001406777.1:c.697C>T NP_001393706.1:p.Arg233Trp missense NM_001406778.1:c.697C>T NP_001393707.1:p.Arg233Trp missense NM_001406784.1:c.433C>T NP_001393713.1:p.Arg145Trp missense NM_020629.2:c.1423C>T NP_065680.1:p.Arg475Trp missense NM_020630.7:c.1423C>T NP_065681.1:p.Arg475Trp missense NC_000010.11:g.43111366C>T NC_000010.10:g.43606814C>T NG_007489.1:g.39298C>T LRG_518:g.39298C>T LRG_518t1:c.1423C>T LRG_518p1:p.Arg475Trp LRG_518t2:c.1423C>T LRG_518p2:p.Arg475Trp - Protein change
- R475W, R221W, R300W, R329W, R145W, R432W, R233W, R343W, R379W
- Other names
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- Canonical SPDI
- NC_000010.11:43111365:C:T
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
- 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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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 |
3446 | 3566 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000693492.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 2, 2018 | RCV000709109.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 27, 2023 | RCV001011519.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 27, 2021 | RCV002499241.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 29, 2022 | RCV003159152.1 |
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
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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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Uncertain significance
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2a
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000838379.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Uncertain significance
(Sep 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 1
Familial medullary thyroid carcinoma MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB Pheochromocytoma MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002784619.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Sep 29, 2022)
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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: SCV003853137.1
First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate secretion efficiency that surpassed wild-type in a quantitative cell-based RET maturation assay and was classified as fully rescuable (Kjaer et al., 2010); Observed in individuals with Hirschsprung disease (Fitze et al., 2002); This variant is associated with the following publications: (PMID: 11955539, 20473317, 14633923, 33193891) (less)
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Uncertain significance
(Mar 27, 2023)
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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: SCV001171850.4
First in ClinVar: Mar 16, 2020 Last updated: Jul 08, 2023 |
Comment:
The p.R475W variant (also known as c.1423C>T), located in coding exon 7 of the RET gene, results from a C to T substitution at nucleotide … (more)
The p.R475W variant (also known as c.1423C>T), located in coding exon 7 of the RET gene, results from a C to T substitution at nucleotide position 1423. The arginine at codon 475 is replaced by tryptophan, an amino acid with dissimilar properties. Structural and functional analyses indicate that this alteration results in protein misfolding (Kjaer S, et al. Hum. Mol. Genet. 2003 Sep;12(17):2133-44; Kjaer S, et al. Nat. Struct. Mol. Biol. 2010 Jun; 17(6):726-31). This alteration has been previously identified in an individual with sporadic Hirschsprung disease (Fitze G, et al. Lancet 2002 Apr; 359(9313):1200-5). It has not been reported in an individual with a diagnosis of multiple endocrine neoplasia type 2 (MEN2) to date. Based on protein sequence alignment, this amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jan 18, 2024)
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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
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Invitae
Accession: SCV000821363.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 475 of the RET protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 475 of the RET protein (p.Arg475Trp). This variant is present in population databases (rs746512075, gnomAD 0.005%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 11955539). ClinVar contains an entry for this variant (Variation ID: 572175). 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 disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 20473317). 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
(Dec 13, 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
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All of Us Research Program, National Institutes of Health
Accession: SCV004830509.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 475 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with tryptophan at codon 475 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant may have a partial or mild impact on RET protein misfolding via indirect proxy assays (PMID: 12915470, 20473317). This variant has not been reported in individuals affected with RET-related cancer in the literature. This variant has been identified in 6/282740 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: 6
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations. | Kjaer S | Nature structural & molecular biology | 2010 | PMID: 20473317 |
Intrinsic susceptibility to misfolding of a hot-spot for Hirschsprung disease mutations in the ectodomain of RET. | Kjaer S | Human molecular genetics | 2003 | PMID: 12915470 |
Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung's disease. | Fitze G | Lancet (London, England) | 2002 | PMID: 11955539 |
Text-mined citations for rs746512075 ...
HelpRecord last updated Apr 20, 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.