Published functional studies demonstrate a damaging effect, with less than 1% residual SPR enzyme activity on western blot analysis (Arrabal et al., 2011); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 11 amino acids are lost (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21677200, 24212389, 22522443, 21431957, 16917893, 25763508, 31589614)
ClinVar Genomic variation as it relates to human health
NM_003124.5(SPR):c.751A>T (p.Lys251Ter)
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_003124.5(SPR):c.751A>T (p.Lys251Ter)
Variation ID: 12944 Accession: VCV000012944.41
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p13.2 2: 72891502 (GRCh38) [ NCBI UCSC ] 2: 73118631 (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 Feb 25, 2014 Oct 20, 2024 Jun 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_003124.5:c.751A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003115.1:p.Lys251Ter nonsense NC_000002.12:g.72891502A>T NC_000002.11:g.73118631A>T NG_008234.1:g.9120A>T - Protein change
- K251*
- Other names
- -
- Canonical SPDI
- NC_000002.12:72891501:A: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00008
- 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. |
|||
| SPR | - | - |
GRCh38 GRCh37 |
185 | 274 | |
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
|
May 25, 2022 | RCV000013807.32 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 2, 2024 | RCV000699300.6 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2024 | RCV000599405.28 |
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
(Jul 18, 2019)
|
criteria provided, single submitter
Method: research
|
Dopa-responsive dystonia due to sepiapterin reductase deficiency
Affected status: yes
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI WGS
Accession: SCV001190877.1 First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Behavioral abnormality (present) , Global developmental delay (present) , Neurodevelopmental delay (present)
|
|
|
Pathogenic
(Nov 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000709983.4
First in ClinVar: Apr 02, 2018 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect, with less than 1% residual SPR enzyme activity on western blot analysis (Arrabal et al., 2011); Nonsense variant … (more)
Published functional studies demonstrate a damaging effect, with less than 1% residual SPR enzyme activity on western blot analysis (Arrabal et al., 2011); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 11 amino acids are lost (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21677200, 24212389, 22522443, 21431957, 16917893, 25763508, 31589614) (less)
|
|
|
Pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Dystonic disorder
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000828005.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys251*) in the SPR gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Lys251*) in the SPR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the SPR protein. This variant is present in population databases (rs121917747, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with SPR-related conditions (PMID: 16917893, 18502672, 21431957, 21677200, 24212389, 25763508, 29116116). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12944). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Dopa-responsive dystonia due to sepiapterin reductase deficiency
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521722.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Stop-gained (nonsense): predicted to result in a … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 21431957). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 21677200) and co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18502672, 21677200). It has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012944 / PMID: 16917893). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Axial hypotonia (present) , Generalized tonic seizure (present) , Bilateral tonic-clonic seizure (present) , Oculogyric crisis (present) , Parkinsonism with favorable response to dopaminergic medication … (more)
Axial hypotonia (present) , Generalized tonic seizure (present) , Bilateral tonic-clonic seizure (present) , Oculogyric crisis (present) , Parkinsonism with favorable response to dopaminergic medication (present) , Bradykinesia (present) , Intellectual disability (present) , Language disorder (present) (less)
|
|
|
Pathogenic
(May 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Dopa-responsive dystonia due to sepiapterin reductase deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021946.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jun 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334865.25
First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024 |
Comment:
SPR: PM3:Strong, PVS1:Strong, PM2:Supporting, PP1, PS3:Supporting
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Aug 01, 2011)
|
no assertion criteria provided
Method: literature only
|
DYSTONIA, DOPA-RESPONSIVE, DUE TO SEPIAPTERIN REDUCTASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034054.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 25, 2014 |
Comment on evidence:
In 2 Greek sibs with SPR deficiency (612716), Verbeek et al. (2008) identified a homozygous 751A-T transversion in the SPR gene, resulting in a lys251-to-ter … (more)
In 2 Greek sibs with SPR deficiency (612716), Verbeek et al. (2008) identified a homozygous 751A-T transversion in the SPR gene, resulting in a lys251-to-ter (K251X) substitution. Each unaffected parent was heterozygous for the mutation. SPR activity was undetectable in patient fibroblasts. In a Spanish boy with classic SPR deficiency, Arrabal et al. (2011) identified a homozygous K251X mutation. The K251X mutation results in an SPR protein with a small C-terminal deletion and no residual activity, as it eliminates a critical residue (D257) involved in substrate binding specificity and anchoring. The patient had onset in infancy of psychomotor retardation, hypotonia, hypersalivation, hypersomnolence, ataxia, and extrapyramidal signs. The diagnosis was made after neurotransmitter analysis and genetic testing. Treatment with L-DOPA and 5-hydroxytryptophan resulted in neurologic improvement, although he still had slight psychomotor delay 3 years later. (less)
|
|
|
Pathogenic
(Aug 13, 2022)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV003840079.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
DNA sequence analysis of the SPR gene demonstrated a sequence change, c.751A>T, which results in the creation of a premature stop codon at amino acid … (more)
DNA sequence analysis of the SPR gene demonstrated a sequence change, c.751A>T, which results in the creation of a premature stop codon at amino acid position 251, p.Lys251*. While this sequence change is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acids of the SPR protein. This sequence change has been described in the gnomAD database with a frequency of 0.01% in the European subpopulation (dbSNP rs121917747). This sequence change has previously been described in individuals with SPR deficiency in both homozygous and the compound heterozygous state (PMID: 21431957,18502672, 25763508,16917893, 24212389) . Functional assay involving western blot analysis showed significantly reduced residual SPR enzyme activity for this sequence change (PMID: 21431957). These collective evidences indicate that this sequence change is pathogenic. (less)
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Lys251*) in the SPR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the SPR protein. This variant is present in population databases (rs121917747, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with SPR-related conditions (PMID: 16917893, 18502672, 21431957, 21677200, 24212389, 25763508, 29116116). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12944). For these reasons, this variant has been classified as Pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 21431957). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 21677200) and co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18502672, 21677200). It has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012944 / PMID: 16917893). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
SPR: PM3:Strong, PVS1:Strong, PM2:Supporting, PP1, PS3:Supporting
Comment:
DNA sequence analysis of the SPR gene demonstrated a sequence change, c.751A>T, which results in the creation of a premature stop codon at amino acid position 251, p.Lys251*. While this sequence change is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acids of the SPR protein. This sequence change has been described in the gnomAD database with a frequency of 0.01% in the European subpopulation (dbSNP rs121917747). This sequence change has previously been described in individuals with SPR deficiency in both homozygous and the compound heterozygous state (PMID: 21431957,18502672, 25763508,16917893, 24212389) . Functional assay involving western blot analysis showed significantly reduced residual SPR enzyme activity for this sequence change (PMID: 21431957). These collective evidences indicate that this sequence change is 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:
Published functional studies demonstrate a damaging effect, with less than 1% residual SPR enzyme activity on western blot analysis (Arrabal et al., 2011); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 11 amino acids are lost (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21677200, 24212389, 22522443, 21431957, 16917893, 25763508, 31589614)
Comment:
This sequence change creates a premature translational stop signal (p.Lys251*) in the SPR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the SPR protein. This variant is present in population databases (rs121917747, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with SPR-related conditions (PMID: 16917893, 18502672, 21431957, 21677200, 24212389, 25763508, 29116116). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12944). For these reasons, this variant has been classified as Pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 21431957). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 21677200) and co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18502672, 21677200). It has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012944 / PMID: 16917893). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
SPR: PM3:Strong, PVS1:Strong, PM2:Supporting, PP1, PS3:Supporting
Comment:
DNA sequence analysis of the SPR gene demonstrated a sequence change, c.751A>T, which results in the creation of a premature stop codon at amino acid position 251, p.Lys251*. While this sequence change is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acids of the SPR protein. This sequence change has been described in the gnomAD database with a frequency of 0.01% in the European subpopulation (dbSNP rs121917747). This sequence change has previously been described in individuals with SPR deficiency in both homozygous and the compound heterozygous state (PMID: 21431957,18502672, 25763508,16917893, 24212389) . Functional assay involving western blot analysis showed significantly reduced residual SPR enzyme activity for this sequence change (PMID: 21431957). These collective evidences indicate that this sequence change is pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Urinary sulphatoxymelatonin as a biomarker of serotonin status in biogenic amine-deficient patients. | Batllori M | Scientific reports | 2017 | PMID: 29116116 |
| Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under L-DOPA, 5-HTP and BH4 Trials. | Mazzuca M | JIMD reports | 2015 | PMID: 25763508 |
| Very early pattern of movement disorders in sepiapterin reductase deficiency. | Leuzzi V | Neurology | 2013 | PMID: 24212389 |
| Whole-genome sequencing for optimized patient management. | Bainbridge MN | Science translational medicine | 2011 | PMID: 21677200 |
| Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant. | Arrabal L | Neurogenetics | 2011 | PMID: 21431957 |
| Two Greek siblings with sepiapterin reductase deficiency. | Verbeek MM | Molecular genetics and metabolism | 2008 | PMID: 18502672 |
| Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. | Thöny B | Human mutation | 2006 | PMID: 16917893 |
Text-mined citations for rs121917747 ...
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 20, 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.