This variant is interpreted as a Pathogenic for Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1-Moderate => PP1 upgraded in strength to Moderate. PS3-Very Strong => PS3 upgraded in strength to Very Strong (PMID:30401461).
ClinVar Genomic variation as it relates to human health
NM_017825.3(ADPRS):c.1004T>G (p.Val335Gly)
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.
(8)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_017825.3(ADPRS):c.1004T>G (p.Val335Gly)
Variation ID: 599343 Accession: VCV000599343.44
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p34.3 1: 36093298 (GRCh38) [ NCBI UCSC ] 1: 36558899 (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 14, 2019 Oct 26, 2024 May 22, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_017825.3:c.1004T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060295.1:p.Val335Gly missense NC_000001.11:g.36093298T>G NC_000001.10:g.36558899T>G NG_016245.2:g.36787A>C - Protein change
- V335G
- Other names
-
ADPRHL2, VAL335GLY (rs201735454)
- Canonical SPDI
- NC_000001.11:36093297:T:G
-
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) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00008
The Genome Aggregation Database (gnomAD) 0.00011
Exome Aggregation Consortium (ExAC) 0.00012
- 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. |
|||
| ADPRS | - | - |
GRCh38 GRCh37 |
63 | 76 | |
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 (7) |
criteria provided, multiple submitters, no conflicts
|
May 22, 2024 | RCV000735981.22 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 1, 2023 | RCV002067181.18 |
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
(Dec 10, 2018)
|
criteria provided, single submitter
Method: curation
|
Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000899138.1
First in ClinVar: Apr 29, 2019 Last updated: Apr 29, 2019
Comment:
ClinGen:CA764739
|
Comment:
This variant is interpreted as a Pathogenic for Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, autosomal recessive. The following ACMG Tag(s) were applied: PM2 … (more)
This variant is interpreted as a Pathogenic for Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1-Moderate => PP1 upgraded in strength to Moderate. PS3-Very Strong => PS3 upgraded in strength to Very Strong (PMID:30401461). (less)
|
|
|
Pathogenic
(Feb 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150002.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
|
|
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Pathogenic
(Dec 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000923706.2
First in ClinVar: Jun 17, 2019 Last updated: Dec 17, 2023 |
Number of individuals with the variant: 1
Geographic origin: Iran
|
|
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Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002496858.18
First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024 |
Comment:
ADPRS: PP1:Strong, PM2, PM3, PP4, PS3:Supporting
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841638.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Functional studies provide moderate evidence of the … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 30401461). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ADPRS related disorder (PMID: 30401461). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 30401461). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar ataxia (present) , Polyneuropathy (present) , Unsteady gait (present)
|
|
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Pathogenic
(May 22, 2024)
|
criteria provided, single submitter
Method: research
|
Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town
Accession: SCV003930343.3
First in ClinVar: Aug 19, 2023 Last updated: May 26, 2024 |
Comment:
PM2_supporting: the highest population allele frequency in gnomAD v4.0 (0.011%; 135/1180056 alleles in European non-Finnish population). PP3 not met: REVEL score is 0.62. PP1_strong: variant … (more)
PM2_supporting: the highest population allele frequency in gnomAD v4.0 (0.011%; 135/1180056 alleles in European non-Finnish population). PP3 not met: REVEL score is 0.62. PP1_strong: variant segregates with 6 informative meioses across 2 families (PMID 30401461, PMID 34479984). PS3_supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product (PMID 30401461, PMID 34479984). PS4 not evaluated as literature probands already counted under PM3. PM3 met: max 1 point awarded for homozygous occurrence of variant in 3 families (PMID: 34479984, PMID 30401461). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: South Africa
|
|
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Pathogenic
(Jan 09, 2019)
|
no assertion criteria provided
Method: literature only
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NEURODEGENERATION, CHILDHOOD-ONSET, STRESS-INDUCED, WITH VARIABLE ATAXIA AND SEIZURES
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000864180.1
First in ClinVar: Jan 14, 2019 Last updated: Jan 14, 2019 |
Comment on evidence:
In 6 patients from 4 unrelated families (families 1, 4, 5, and 6) with stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS; 618170), Danhauser … (more)
In 6 patients from 4 unrelated families (families 1, 4, 5, and 6) with stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS; 618170), Danhauser et al. (2018) identified a homozygous c.1004T-G transversion (c.1004T-G, NM_017825.2) in exon 6 of the ADPRHL2 gene, resulting in a val335-to-gly (V335G) substitution at a conserved residue in the glycohydrolase domain. The mutation, which was found by exome sequencing, segregated with the disorder in the families. The variant was found at a low frequency in the heterozygous state in the gnomAD database (27 of 277,240 alleles). The families were of various ethnic origins, including German, Kosovan, and Polish, and haplotype analysis indicated a founder effect. Patient fibroblasts showed undetectable ADPRHL2 protein as well as impaired cellular removal of ADP-ribose, accumulation of PAR, and reduced viability compared to wildtype when stressed with hydrogen peroxide. The reduced viability and PAR accumulation could be rescued with wildtype ADPRHL2 and with a PARP1 (173870) inhibitor. These findings were consistent with the mutation causing a loss of function. (less)
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|
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Likely pathogenic
(Jun 01, 2022)
|
no assertion criteria provided
Method: provider interpretation
|
Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures
Affected status: yes
Allele origin:
inherited
|
Solve-RD Consortium
Accession: SCV005091407.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
|
Comment:
Variant confirmed as disease-causing by referring clinical team
|
Comment:
Comment:
ADPRS: PP1:Strong, PM2, PM3, PP4, PS3:Supporting
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 30401461). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ADPRS related disorder (PMID: 30401461). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 30401461). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PM2_supporting: the highest population allele frequency in gnomAD v4.0 (0.011%; 135/1180056 alleles in European non-Finnish population). PP3 not met: REVEL score is 0.62. PP1_strong: variant segregates with 6 informative meioses across 2 families (PMID 30401461, PMID 34479984). PS3_supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product (PMID 30401461, PMID 34479984). PS4 not evaluated as literature probands already counted under PM3. PM3 met: max 1 point awarded for homozygous occurrence of variant in 3 families (PMID: 34479984, PMID 30401461). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
Comment:
Variant confirmed as disease-causing by referring clinical team
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 variant is interpreted as a Pathogenic for Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1-Moderate => PP1 upgraded in strength to Moderate. PS3-Very Strong => PS3 upgraded in strength to Very Strong (PMID:30401461).
Comment:
ADPRS: PP1:Strong, PM2, PM3, PP4, PS3:Supporting
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 30401461). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ADPRS related disorder (PMID: 30401461). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 30401461). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PM2_supporting: the highest population allele frequency in gnomAD v4.0 (0.011%; 135/1180056 alleles in European non-Finnish population). PP3 not met: REVEL score is 0.62. PP1_strong: variant segregates with 6 informative meioses across 2 families (PMID 30401461, PMID 34479984). PS3_supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product (PMID 30401461, PMID 34479984). PS4 not evaluated as literature probands already counted under PM3. PM3 met: max 1 point awarded for homozygous occurrence of variant in 3 families (PMID: 34479984, PMID 30401461). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia. | Mahungu AC | Frontiers in neurology | 2023 | PMID: 37712079 |
| Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy. | Danhauser K | American journal of human genetics | 2018 | PMID: 30401461 |
Text-mined citations for rs201735454 ...
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 Oct 27, 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.