Identified in patients in published literature with biochemical evidence of dihydropyrimidinase deficiency, but no definitively related symptoms (Nakajima et al., 2017; Tsuchiya et al., 2019); Published functional studies demonstrate a damaging effect: reduced DHP activity (Nakajima et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29054612, 30384990, 34426522, 32619063, 32707991)
ClinVar Genomic variation as it relates to human health
NM_001385.3(DPYS):c.1469G>A (p.Arg490His)
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.
(6)
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
6
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.1469G>A (p.Arg490His)
Variation ID: 909729 Accession: VCV000909729.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 8q22.3 8: 104381289 (GRCh38) [ NCBI UCSC ] 8: 105393517 (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 May 31, 2020 Nov 24, 2024 Oct 9, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001385.3:c.1469G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001376.1:p.Arg490His missense NC_000008.11:g.104381289C>T NC_000008.10:g.105393517C>T NG_008840.2:g.90761G>A - Protein change
- R490H
- Other names
-
DPYS, ARG490HIS (rs189448963)
- Canonical SPDI
- NC_000008.11:104381288:C:T
-
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.
-
0.00080 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00018
The Genome Aggregation Database (gnomAD) 0.00021
Exome Aggregation Consortium (ExAC) 0.00023
The Genome Aggregation Database (gnomAD), exomes 0.00024
1000 Genomes Project 0.00080
1000 Genomes Project 30x 0.00094
- 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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 9, 2024 | RCV001160988.9 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 13, 2022 | RCV001882508.8 | |
|
DPYS-related disorder
|
Likely pathogenic (1) |
no assertion criteria provided
|
Sep 4, 2024 | RCV004756182.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Aug 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002559664.2
First in ClinVar: Aug 15, 2022 Last updated: Mar 04, 2023 |
Comment:
Identified in patients in published literature with biochemical evidence of dihydropyrimidinase deficiency, but no definitively related symptoms (Nakajima et al., 2017; Tsuchiya et al., 2019); … (more)
Identified in patients in published literature with biochemical evidence of dihydropyrimidinase deficiency, but no definitively related symptoms (Nakajima et al., 2017; Tsuchiya et al., 2019); Published functional studies demonstrate a damaging effect: reduced DHP activity (Nakajima et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29054612, 30384990, 34426522, 32619063, 32707991) (less)
|
|
|
Pathogenic
(Sep 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002210787.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg490 amino acid residue in DPYS. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg490 amino acid residue in DPYS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20362666, 29054612). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects DPYS function (PMID: 29054612). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 909729). This missense change has been observed in individual(s) with dihydropyrimidinase deficiency (PMID: 29054612, 30384990). This variant is present in population databases (rs189448963, gnomAD 0.1%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 490 of the DPYS protein (p.Arg490His). (less)
|
|
|
Likely pathogenic
(Sep 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Dihydropyrimidinase deficiency
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV001322831.2
First in ClinVar: May 31, 2020 Last updated: Oct 13, 2024 |
|
|
|
Pathogenic
(Oct 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Dihydropyrimidinase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005399919.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Dihydropyrimidinase deficiency (MIM#222748). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. The clinical presentation can be highly variable, with compound heterozygous or homozygous individuals also reported as asymptomatic (OMIM, PMID: 20362666). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (333 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4) (78 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Arg490Cys) has been reported as homozygous or compound heterozygous in multiple affected individuals (ClinVar, PMIDs: 32472544, 20362666, 29054612), while p.(Arg490Thr) has been reported in an unaffected individual (PMID:9718352). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. There have been several reports of affected individuals with this variant (ClinVar, PMID: 29054612). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant shows reduced enzymatic activity compared to wildtype, and an inability to form oligomers (PMIDs: 29054612). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Jul 17, 2020)
|
no assertion criteria provided
Method: literature only
|
DIHYDROPYRIMIDINASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001422325.2
First in ClinVar: Jul 16, 2020 Last updated: Dec 31, 2022 |
Comment on evidence:
For discussion of the c.1469G-A transition in the DPYS gene, resulting in an arg490-to-his (R490H) substitution, that was found in a Japanese girl with dihydropyrimidinase … (more)
For discussion of the c.1469G-A transition in the DPYS gene, resulting in an arg490-to-his (R490H) substitution, that was found in a Japanese girl with dihydropyrimidinase deficiency (DPYS; 222748) by Nakajima et al. (2017), see 613326.0005. (less)
|
|
|
Likely pathogenic
(Sep 04, 2024)
|
no assertion criteria provided
Method: clinical testing
|
DPYS-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005352350.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The DPYS c.1469G>A variant is predicted to result in the amino acid substitution p.Arg490His. This variant was reported in individuals with dihydropyrimidinase deficiency (Nakajima et … (more)
The DPYS c.1469G>A variant is predicted to result in the amino acid substitution p.Arg490His. This variant was reported in individuals with dihydropyrimidinase deficiency (Nakajima et al. 2017. PubMed ID: 29054612, Tsuchiya et al. 2018. PubMed ID: 30384990). In vitro functional characterization showed that it leads to diminished DHP activity (Nakajima et al. 2017. PubMed ID: 29054612). This variant is reported in 0.11% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg490 amino acid residue in DPYS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20362666, 29054612). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects DPYS function (PMID: 29054612). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 909729). This missense change has been observed in individual(s) with dihydropyrimidinase deficiency (PMID: 29054612, 30384990). This variant is present in population databases (rs189448963, gnomAD 0.1%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 490 of the DPYS protein (p.Arg490His).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Dihydropyrimidinase deficiency (MIM#222748). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. The clinical presentation can be highly variable, with compound heterozygous or homozygous individuals also reported as asymptomatic (OMIM, PMID: 20362666). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (333 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4) (78 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Arg490Cys) has been reported as homozygous or compound heterozygous in multiple affected individuals (ClinVar, PMIDs: 32472544, 20362666, 29054612), while p.(Arg490Thr) has been reported in an unaffected individual (PMID:9718352). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. There have been several reports of affected individuals with this variant (ClinVar, PMID: 29054612). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant shows reduced enzymatic activity compared to wildtype, and an inability to form oligomers (PMIDs: 29054612). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The DPYS c.1469G>A variant is predicted to result in the amino acid substitution p.Arg490His. This variant was reported in individuals with dihydropyrimidinase deficiency (Nakajima et al. 2017. PubMed ID: 29054612, Tsuchiya et al. 2018. PubMed ID: 30384990). In vitro functional characterization showed that it leads to diminished DHP activity (Nakajima et al. 2017. PubMed ID: 29054612). This variant is reported in 0.11% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.
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:
Identified in patients in published literature with biochemical evidence of dihydropyrimidinase deficiency, but no definitively related symptoms (Nakajima et al., 2017; Tsuchiya et al., 2019); Published functional studies demonstrate a damaging effect: reduced DHP activity (Nakajima et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29054612, 30384990, 34426522, 32619063, 32707991)
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg490 amino acid residue in DPYS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20362666, 29054612). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects DPYS function (PMID: 29054612). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 909729). This missense change has been observed in individual(s) with dihydropyrimidinase deficiency (PMID: 29054612, 30384990). This variant is present in population databases (rs189448963, gnomAD 0.1%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 490 of the DPYS protein (p.Arg490His).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Dihydropyrimidinase deficiency (MIM#222748). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. The clinical presentation can be highly variable, with compound heterozygous or homozygous individuals also reported as asymptomatic (OMIM, PMID: 20362666). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (333 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4) (78 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Arg490Cys) has been reported as homozygous or compound heterozygous in multiple affected individuals (ClinVar, PMIDs: 32472544, 20362666, 29054612), while p.(Arg490Thr) has been reported in an unaffected individual (PMID:9718352). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. There have been several reports of affected individuals with this variant (ClinVar, PMID: 29054612). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant shows reduced enzymatic activity compared to wildtype, and an inability to form oligomers (PMIDs: 29054612). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The DPYS c.1469G>A variant is predicted to result in the amino acid substitution p.Arg490His. This variant was reported in individuals with dihydropyrimidinase deficiency (Nakajima et al. 2017. PubMed ID: 29054612, Tsuchiya et al. 2018. PubMed ID: 30384990). In vitro functional characterization showed that it leads to diminished DHP activity (Nakajima et al. 2017. PubMed ID: 29054612). This variant is reported in 0.11% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Functional Characterization of 12 Dihydropyrimidinase Allelic Variants in Japanese Individuals for the Prediction of 5-Fluorouracil Treatment-Related Toxicity. | Hishinuma E | Drug metabolism and disposition: the biological fate of chemicals | 2023 | PMID: 36414408 |
| [Analysis of DPYS gene variants in a child with dihydropyrimidase deficiency]. | Lei M | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2020 | PMID: 32472544 |
| A case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis. | Tsuchiya H | Brain & development | 2019 | PMID: 30384990 |
| Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity. | Nakajima Y | Molecular genetics and metabolism | 2017 | PMID: 29054612 |
| Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients. | van Kuilenburg AB | Biochimica et biophysica acta | 2010 | PMID: 20362666 |
| Dihydropyrimidinase deficiency: structural organization, chromosomal localization, and mutation analysis of the human dihydropyrimidinase gene. | Hamajima N | American journal of human genetics | 1998 | PMID: 9718352 |
Text-mined citations for rs189448963 ...
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 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.