In vitro assays demonstrate N173S loss of function (Ganapathi M, 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30661771, 34273022)
ClinVar Genomic variation as it relates to human health
NM_001930.4(DHPS):c.518A>G (p.Asn173Ser)
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_001930.4(DHPS):c.518A>G (p.Asn173Ser)
Variation ID: 560194 Accession: VCV000560194.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.13 19: 12679696 (GRCh38) [ NCBI UCSC ] 19: 12790510 (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.518A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001921.1:p.Asn173Ser missense NM_001206974.2:c.392A>G NP_001193903.1:p.Asn131Ser missense NM_001369691.1:c.518A>G NP_001356620.1:p.Asn173Ser missense NM_001369692.1:c.518A>G NP_001356621.1:p.Asn173Ser missense NM_001369693.1:c.-32A>G 5 prime UTR NM_013406.3:c.518A>G NP_037538.1:p.Asn173Ser missense NR_038192.2:n.632A>G non-coding transcript variant NR_161467.1:n.649A>G non-coding transcript variant NR_161468.1:n.632A>G non-coding transcript variant NR_161469.1:n.632A>G non-coding transcript variant NC_000019.10:g.12679696T>C NC_000019.9:g.12790510T>C - Protein change
- N173S, N131S
- Other names
- -
- Canonical SPDI
- NC_000019.10:12679695:T:C
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00009
- 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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 5, 2022 | RCV000754487.4 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 9, 2024 | RCV000786000.4 | |
|
DHPS-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Feb 21, 2023 | RCV003403569.4 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000804205.3
First in ClinVar: Jan 28, 2019 Last updated: Mar 04, 2023 |
Comment:
In vitro assays demonstrate N173S loss of function (Ganapathi M, 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; … (more)
In vitro assays demonstrate N173S loss of function (Ganapathi M, 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30661771, 34273022) (less)
|
|
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Pathogenic
(Feb 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
DHPS-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004119572.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The DHPS c.518A>G variant is predicted to result in the amino acid substitution p.Asn173Ser. This variant was reported in the compound heterozygous state, in trans … (more)
The DHPS c.518A>G variant is predicted to result in the amino acid substitution p.Asn173Ser. This variant was reported in the compound heterozygous state, in trans with a predicted loss-of-function variant, in all five affected individuals described in the DHPS index study (Ganapathi et al 2019. PubMed ID: 30661771). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-12790510-T-C). This variant is interpreted as pathogenic. (less)
|
|
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Likely pathogenic
(Oct 22, 2019)
|
criteria provided, single submitter
Method: curation
|
Neurodevelopmental disorder with seizures and speech and walking impairment
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV001194270.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
This variant is interpreted as Likely pathogenic for Neurodevelopmental disorder with seizures and speech and walking impairment, autosomal recessive. The following ACMG Tag(s) were applied: … (more)
This variant is interpreted as Likely pathogenic for Neurodevelopmental disorder with seizures and speech and walking impairment, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PP1, PM3, PS3-Moderate. (less)
|
|
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Pathogenic
(Apr 22, 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: SCV004801470.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The DHPS c.518A>G (p.Asn173Ser) variant is a missense variant, which has been identified in a compound heterozygous state in at least five individuals with neurodevelopmental … (more)
The DHPS c.518A>G (p.Asn173Ser) variant is a missense variant, which has been identified in a compound heterozygous state in at least five individuals with neurodevelopmental disorder from four unrelated families (Ganapathi et al. 2019). The p.Asn173Ser variant is reported at a frequency of 0.000116 in the European (non-Finnish) population in the Genome Aggregation Database (version 2.1.1). Functional studies demonstrate that the p.(Asn173Ser) variant exhibited partial enzymatic activity, ranging from 18% to 25% of that of wild-type DHPS resulting in impaired biosynthesis of deoxyhypusine (Ganapathi et al. 2019). Based on the collective evidence the c.518A>G (p.Asn173Ser) variant is classified as 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: SCV005398248.1
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) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated deoxyhypusine synthase domain (DECIPHER). (I) 0705 - No comparable missense 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 pathogenic three times (ClinVar) and in five affected individuals from four unrelated families who were compound heterozygous for this variant (PMID: 30661771). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cell lines with the p.(Asn173Ser) variant demonstrated only partial enzyme activity, approximately 20% of wild type enzymatic activity (PMID:30661771). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001930.3:c.1014+1G>A) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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|
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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: SCV000924639.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment on evidence:
In 5 patients from 4 unrelated families with neurodevelopmental disorder with seizures and speech and walking impairment (NEDSSWI; 618480) Ganapathi et al. (2019) identified compound … (more)
In 5 patients from 4 unrelated families with neurodevelopmental disorder with seizures and speech and walking impairment (NEDSSWI; 618480) Ganapathi et al. (2019) identified compound heterozygous mutations in the DHPS gene. All patients carried a heterozygous c.518A-G transition (c.518A-G, NM_001930.3) in exon 3, resulting in an asn173-to-ser (N173S) substitution at a highly conserved residue, on 1 allele in trans with a likely disrupting variant on the other allele. On the other allele, 3 patients (2 sibs from family 1 and patient 4, an 8-year-old girl from family 3) had a G-to-A transition in intron 8 (c.1014+1G-A; 600944.0002); a 7-year-old girl (patient 3 from family 2) had a 6-bp in-frame deletion (c.912_917delTTACAT; 600944.0003) resulting in the deletion of highly conserved residues (Tyr305_Ile306del); and a 24-year-old woman (patient 5 from family 4) had a c.1A-G transition, resulting in a met1-to-? (M1?; 600944.0004) substitution. The mutations, which were found by exome sequencing, segregated with the disorder in all families. All except the 6-bp deletion, which was not found in gnomAD, were found at very low frequencies in the gnomAD database, all in the heterozygous state. Haplotype analysis suggested a distant common ancestor for the N173S variant between families 1, 3, and 4, whereas family 2 had a different haplotype. The splice site variant was demonstrated to caused production of an abnormal transcript that, if translated, was predicted to cause premature termination with absence of the active site of the enzyme. In vitro functional expression studies of the purified enzyme in E. coli showed that the N173S and Y305_I306del variants had impaired biosynthesis of deoxyhypusine compared to wildtype, with the Y305_I306del variant being almost completely devoid of enzyme activity. The N173S variant retained some partial activity (about 18 to 25% of wildtype). These findings were verified by further studies of hypusination of eIF5A (600187) in HEK293 cells, which was significantly decreased by both variants, with a more severe effect by Y305_I306del. (less)
|
Comment:
Comment:
The DHPS c.518A>G variant is predicted to result in the amino acid substitution p.Asn173Ser. This variant was reported in the compound heterozygous state, in trans with a predicted loss-of-function variant, in all five affected individuals described in the DHPS index study (Ganapathi et al 2019. PubMed ID: 30661771). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-12790510-T-C). This variant is interpreted as pathogenic.
Comment:
This variant is interpreted as Likely pathogenic for Neurodevelopmental disorder with seizures and speech and walking impairment, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PP1, PM3, PS3-Moderate.
Comment:
The DHPS c.518A>G (p.Asn173Ser) variant is a missense variant, which has been identified in a compound heterozygous state in at least five individuals with neurodevelopmental disorder from four unrelated families (Ganapathi et al. 2019). The p.Asn173Ser variant is reported at a frequency of 0.000116 in the European (non-Finnish) population in the Genome Aggregation Database (version 2.1.1). Functional studies demonstrate that the p.(Asn173Ser) variant exhibited partial enzymatic activity, ranging from 18% to 25% of that of wild-type DHPS resulting in impaired biosynthesis of deoxyhypusine (Ganapathi et al. 2019). Based on the collective evidence the c.518A>G (p.Asn173Ser) variant is classified as 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) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated deoxyhypusine synthase domain (DECIPHER). (I) 0705 - No comparable missense 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 pathogenic three times (ClinVar) and in five affected individuals from four unrelated families who were compound heterozygous for this variant (PMID: 30661771). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cell lines with the p.(Asn173Ser) variant demonstrated only partial enzyme activity, approximately 20% of wild type enzymatic activity (PMID:30661771). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001930.3:c.1014+1G>A) in a recessive disease. (I) 1205 - This variant has been shown to be maternally 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:
In vitro assays demonstrate N173S loss of function (Ganapathi M, 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30661771, 34273022)
Comment:
The DHPS c.518A>G variant is predicted to result in the amino acid substitution p.Asn173Ser. This variant was reported in the compound heterozygous state, in trans with a predicted loss-of-function variant, in all five affected individuals described in the DHPS index study (Ganapathi et al 2019. PubMed ID: 30661771). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-12790510-T-C). This variant is interpreted as pathogenic.
Comment:
This variant is interpreted as Likely pathogenic for Neurodevelopmental disorder with seizures and speech and walking impairment, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PP1, PM3, PS3-Moderate.
Comment:
The DHPS c.518A>G (p.Asn173Ser) variant is a missense variant, which has been identified in a compound heterozygous state in at least five individuals with neurodevelopmental disorder from four unrelated families (Ganapathi et al. 2019). The p.Asn173Ser variant is reported at a frequency of 0.000116 in the European (non-Finnish) population in the Genome Aggregation Database (version 2.1.1). Functional studies demonstrate that the p.(Asn173Ser) variant exhibited partial enzymatic activity, ranging from 18% to 25% of that of wild-type DHPS resulting in impaired biosynthesis of deoxyhypusine (Ganapathi et al. 2019). Based on the collective evidence the c.518A>G (p.Asn173Ser) variant is classified as 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) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated deoxyhypusine synthase domain (DECIPHER). (I) 0705 - No comparable missense 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 pathogenic three times (ClinVar) and in five affected individuals from four unrelated families who were compound heterozygous for this variant (PMID: 30661771). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cell lines with the p.(Asn173Ser) variant demonstrated only partial enzyme activity, approximately 20% of wild type enzymatic activity (PMID:30661771). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001930.3:c.1014+1G>A) in a recessive disease. (I) 1205 - This variant has been shown to be maternally 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 rs758100382 ...
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.