The c.1014+1G>A variant in the DHPS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 8. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Although not identified in the homozygous state, the c.1014+1G>A variant is observed in 13/10,098 (0.13%) alleles from individuals of Ashkenazi Jewish background, and in 118/276,550 total alleles, in large population cohorts (Lek et al., 2016). We interpret c.1014+1G>A as a variant of uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_001930.4(DHPS):c.1014+1G>A
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(4); Uncertain significance(1)
Pathogenic(1); Likely pathogenic(4); Uncertain significance(1)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001930.4(DHPS):c.1014+1G>A
Variation ID: 560196 Accession: VCV000560196.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.13 19: 12676016 (GRCh38) [ NCBI UCSC ] 19: 12786830 (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 Jan 28, 2019 Nov 24, 2024 Oct 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001930.4:c.1014+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001206974.2:c.888+1G>A splice donor NM_001369691.1:c.950+1G>A splice donor NM_001369692.1:c.785-140G>A intron variant NM_001369693.1:c.465+1G>A splice donor NM_013406.3:c.873+1G>A splice donor NC_000019.10:g.12676016C>T NC_000019.9:g.12786830C>T NG_015814.1:g.14213C>T - Protein change
- -
- Other names
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IVS8DS, G-A, +1
- Canonical SPDI
- NC_000019.10:12676015: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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
Trans-Omics for Precision Medicine (TOPMed) 0.00025
The Genome Aggregation Database (gnomAD) 0.00028
Exome Aggregation Consortium (ExAC) 0.00032
The Genome Aggregation Database (gnomAD), exomes 0.00042
- 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. |
|||
| DHPS | - | - |
GRCh38 GRCh37 |
28 | 78 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Feb 21, 2021 | RCV000754489.3 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 9, 2024 | RCV000786001.10 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jul 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000804207.1
First in ClinVar: Jan 28, 2019 Last updated: Jan 28, 2019 |
Comment:
The c.1014+1G>A variant in the DHPS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This … (more)
The c.1014+1G>A variant in the DHPS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 8. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Although not identified in the homozygous state, the c.1014+1G>A variant is observed in 13/10,098 (0.13%) alleles from individuals of Ashkenazi Jewish background, and in 118/276,550 total alleles, in large population cohorts (Lek et al., 2016). We interpret c.1014+1G>A as a variant of uncertain significance. (less)
|
|
|
Likely pathogenic
(Feb 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502711.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: yes
|
|
|
Likely pathogenic
(Jan 25, 2022)
|
criteria provided, single submitter
Method: research
|
Neurodevelopmental disorder with seizures and speech and walking impairment
Affected status: unknown
Allele origin:
unknown
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: CSER_NCGENES_2
Accession: SCV002587030.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022
Comment:
The DHPS c.1014+1G>A variant is predicted to disrupt a canonical splice donor site. This variant is observed in gnomAD v2.1.1 with a global minor allele … (more)
The DHPS c.1014+1G>A variant is predicted to disrupt a canonical splice donor site. This variant is observed in gnomAD v2.1.1 with a global minor allele frequency of 0.04% (120 alleles/282,232 alleles, 0 homozygotes). DHPS c.1014+1G>A has been previously reported in trans with DHPS c.518A>G p.(Asn173Ser) in multiple individuals with an autosomal recessive neurodevelopmental disorder (PMID 30661771). Analysis of RNA from an affected individual suggests this variant results in exon 7 and 8 skipping and introduction of a frameshift and premature termination codon in the last exon (PMID 30661771). Therefore, this variant is classified as likely pathogenic. (less)
|
Number of individuals with the variant: 1
Clinical Features:
Hypospadias (present) , Hypertelorism (present) , Facial asymmetry (present) , Preauricular skin tag (present) , Mixed hearing impairment (present) , Telecanthus (present) , Autism (present) … (more)
Hypospadias (present) , Hypertelorism (present) , Facial asymmetry (present) , Preauricular skin tag (present) , Mixed hearing impairment (present) , Telecanthus (present) , Autism (present) , Intellectual disability, mild (present) , Spasticity (present) , Lower limb spasticity (present) , Spastic paraparesis (present) , Craniofacial asymmetry (present) , Aplasia/Hypoplasia of the external ear (present) , Hemifacial hypoplasia (present) (less)
|
|
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Likely pathogenic
(Dec 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with seizures and speech and walking impairment
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003799047.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
PS3, PM3, PP1
|
|
|
Likely pathogenic
(Apr 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with seizures and speech and walking impairment
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004801429.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The DHPS c.1014+1G>A variant results in a substitution at the consensus splice acceptor site, which is has been shown to result in removal of coding … (more)
The DHPS c.1014+1G>A variant results in a substitution at the consensus splice acceptor site, which is has been shown to result in removal of coding exons 7 and 8 and a premature termination of the protein (Ganapathi et al. 2019). This variant has been identified in individuals with a phenotype consistent with a neurodevelopmental disorder from two unrelated families (Ganapathi et al. 2019). The highest frequency of this allele in the Genome Aggregation Database is 0.001358 in the Ashkenazi Jewish population (version 2.1.1). Functional studies show that the c.1014+1G>A variant Based on the evidence the c.1014+1G>A variant is classified as likely pathogenic for neurodevelopmental disorder with seizures and speech and walking impairment (less)
|
|
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Pathogenic
(Oct 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with seizures and speech and walking impairment
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005398254.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, 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_v1.3.4, 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 neurodevelopmental disorder with seizures and speech and walking impairment (MIM#618480). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. cDNA analysis demonstrates this variant results in exon skipping, however, the protein outcome is uncertain (PMID: 30661771). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (120 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic three times in ClinVar and has been reported as compound heterozygous with p.(Asn173Ser) in three affected individuals from two families (PMID: 30661771). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001930.3:c.518A>G) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
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Pathogenic
(Jun 24, 2019)
|
no assertion criteria provided
Method: literature only
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NEURODEVELOPMENTAL DISORDER WITH SEIZURES AND SPEECH AND WALKING IMPAIRMENT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000924640.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment on evidence:
For discussion of the G-to-A transition in intron 8 (c.1014+1G-A, NM_001930.3) of the in the DHPS gene, resulting in splice site alteration, that was found … (more)
For discussion of the G-to-A transition in intron 8 (c.1014+1G-A, NM_001930.3) of the in the DHPS gene, resulting in splice site alteration, that was found in compound heterozygous state in patients with neurodevelopmental disorder with seizures and speech and walking impairment (NEDSSWI; 618480) by Ganapathi et al. (2019), see 600944.0001. (less)
|
Comment:
Comment:
PS3, PM3, PP1
Comment:
The DHPS c.1014+1G>A variant results in a substitution at the consensus splice acceptor site, which is has been shown to result in removal of coding exons 7 and 8 and a premature termination of the protein (Ganapathi et al. 2019). This variant has been identified in individuals with a phenotype consistent with a neurodevelopmental disorder from two unrelated families (Ganapathi et al. 2019). The highest frequency of this allele in the Genome Aggregation Database is 0.001358 in the Ashkenazi Jewish population (version 2.1.1). Functional studies show that the c.1014+1G>A variant Based on the evidence the c.1014+1G>A variant is classified as likely pathogenic for neurodevelopmental disorder with seizures and speech and walking impairment
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, 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 neurodevelopmental disorder with seizures and speech and walking impairment (MIM#618480). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. cDNA analysis demonstrates this variant results in exon skipping, however, the protein outcome is uncertain (PMID: 30661771). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (120 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic three times in ClinVar and has been reported as compound heterozygous with p.(Asn173Ser) in three affected individuals from two families (PMID: 30661771). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001930.3:c.518A>G) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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.1014+1G>A variant in the DHPS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 8. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Although not identified in the homozygous state, the c.1014+1G>A variant is observed in 13/10,098 (0.13%) alleles from individuals of Ashkenazi Jewish background, and in 118/276,550 total alleles, in large population cohorts (Lek et al., 2016). We interpret c.1014+1G>A as a variant of uncertain significance.
Comment:
PS3, PM3, PP1
Comment:
The DHPS c.1014+1G>A variant results in a substitution at the consensus splice acceptor site, which is has been shown to result in removal of coding exons 7 and 8 and a premature termination of the protein (Ganapathi et al. 2019). This variant has been identified in individuals with a phenotype consistent with a neurodevelopmental disorder from two unrelated families (Ganapathi et al. 2019). The highest frequency of this allele in the Genome Aggregation Database is 0.001358 in the Ashkenazi Jewish population (version 2.1.1). Functional studies show that the c.1014+1G>A variant Based on the evidence the c.1014+1G>A variant is classified as likely pathogenic for neurodevelopmental disorder with seizures and speech and walking impairment
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, 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 neurodevelopmental disorder with seizures and speech and walking impairment (MIM#618480). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. cDNA analysis demonstrates this variant results in exon skipping, however, the protein outcome is uncertain (PMID: 30661771). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (120 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic three times in ClinVar and has been reported as compound heterozygous with p.(Asn173Ser) in three affected individuals from two families (PMID: 30661771). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001930.3:c.518A>G) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder. | Ganapathi M | American journal of human genetics | 2019 | PMID: 30661771 |
Text-mined citations for rs142633494 ...
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.