This sequence change creates a premature translational stop signal (p.Arg475*) in the DPYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DPYS are known to be pathogenic (PMID: 20362666). This variant is present in population databases (rs61758444, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with dihydropyrimidinuria (PMID: 20362666). ClinVar contains an entry for this variant (Variation ID: 446083). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DPYS function (PMID: 20362666, 28642038). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001385.3(DPYS):c.1423C>T (p.Arg475Ter)
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.
Pathogenic/Likely pathogenic
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_001385.3(DPYS):c.1423C>T (p.Arg475Ter)
Variation ID: 446083 Accession: VCV000446083.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q22.3 8: 104392804 (GRCh38) [ NCBI UCSC ] 8: 105405032 (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 5, 2017 Sep 29, 2024 Jul 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001385.3:c.1423C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001376.1:p.Arg475Ter nonsense NC_000008.11:g.104392804G>A NC_000008.10:g.105405032G>A NG_008840.2:g.79246C>T - Protein change
- R475*
- Other names
- -
- Canonical SPDI
- NC_000008.11:104392803:G:A
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00011
Exome Aggregation Consortium (ExAC) 0.00013
The Genome Aggregation Database (gnomAD), exomes 0.00014
Trans-Omics for Precision Medicine (TOPMed) 0.00014
- 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. |
|||
| DPYS | - | - |
GRCh38 GRCh37 |
193 | 238 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 12, 2024 | RCV000514407.10 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 5, 2024 | RCV001783010.6 |
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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Pathogenic
(Jul 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000611076.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446638.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Severe global developmental delay (present) , Microcephaly (present)
Sex: female
|
|
|
Likely pathogenic
(Oct 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Dihydropyrimidinase deficiency
Affected status: unknown
Allele origin:
inherited
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002564242.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
Clinical Features:
Intellectual disability (present) , Seizure (present) , Cerebral palsy (present)
Secondary finding: no
|
|
|
Pathogenic
(Jan 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003263524.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg475*) in the DPYS gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg475*) in the DPYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DPYS are known to be pathogenic (PMID: 20362666). This variant is present in population databases (rs61758444, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with dihydropyrimidinuria (PMID: 20362666). ClinVar contains an entry for this variant (Variation ID: 446083). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DPYS function (PMID: 20362666, 28642038). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Dihydropyrimidinase deficiency
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809388.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
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Pathogenic
(Jul 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Dihydropyrimidinase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005203632.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: DPYS c.1423C>T (p.Arg475X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: DPYS c.1423C>T (p.Arg475X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00014 in 251044 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DPYS causing Dihydropyrimidinase Deficiency, allowing no conclusion about variant significance. c.1423C>T has been reported in the literature in at least one homozygous individual affected with Dihydropyrimidinase Deficiency (e.g. vanKuilenburg_2010). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (e.g. vanKuilenburg_2010). ClinVar contains an entry for this variant (Variation ID: 446083). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002578462.4
First in ClinVar: Oct 15, 2022 Last updated: Sep 29, 2024 |
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity and reduced protein stability (PMID: 20362666, 28642038); Nonsense variant in the C-terminus … (more)
Published functional studies found this variant is associated with significantly reduced enzyme activity and reduced protein stability (PMID: 20362666, 28642038); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 25525159, 31589614, 28642038, 34426522, 20362666) (less)
|
Comment:
Comment:
Variant summary: DPYS c.1423C>T (p.Arg475X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00014 in 251044 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DPYS causing Dihydropyrimidinase Deficiency, allowing no conclusion about variant significance. c.1423C>T has been reported in the literature in at least one homozygous individual affected with Dihydropyrimidinase Deficiency (e.g. vanKuilenburg_2010). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (e.g. vanKuilenburg_2010). ClinVar contains an entry for this variant (Variation ID: 446083). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity and reduced protein stability (PMID: 20362666, 28642038); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 25525159, 31589614, 28642038, 34426522, 20362666)
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 creates a premature translational stop signal (p.Arg475*) in the DPYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DPYS are known to be pathogenic (PMID: 20362666). This variant is present in population databases (rs61758444, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with dihydropyrimidinuria (PMID: 20362666). ClinVar contains an entry for this variant (Variation ID: 446083). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DPYS function (PMID: 20362666, 28642038). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: DPYS c.1423C>T (p.Arg475X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00014 in 251044 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DPYS causing Dihydropyrimidinase Deficiency, allowing no conclusion about variant significance. c.1423C>T has been reported in the literature in at least one homozygous individual affected with Dihydropyrimidinase Deficiency (e.g. vanKuilenburg_2010). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (e.g. vanKuilenburg_2010). ClinVar contains an entry for this variant (Variation ID: 446083). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity and reduced protein stability (PMID: 20362666, 28642038); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 25525159, 31589614, 28642038, 34426522, 20362666)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Functional characterization of 21 allelic variants of dihydropyrimidinase. | Hishinuma E | Biochemical pharmacology | 2017 | PMID: 28642038 |
| Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients. | van Kuilenburg AB | Biochimica et biophysica acta | 2010 | PMID: 20362666 |
Text-mined citations for rs61758444 ...
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.