For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1810). This premature translational stop signal has been observed in individuals with Legius syndrome (PMID: 17704776, 19920235, 21089071). This variant is present in population databases (rs121434313, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg24*) in the SPRED1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPRED1 are known to be pathogenic (PMID: 17704776).
ClinVar Genomic variation as it relates to human health
NM_152594.3(SPRED1):c.70C>T (p.Arg24Ter)
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
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_152594.3(SPRED1):c.70C>T (p.Arg24Ter)
Variation ID: 1810 Accession: VCV000001810.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q14 15: 38299410 (GRCh38) [ NCBI UCSC ] 15: 38591611 (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 Oct 10, 2018 Oct 20, 2024 Sep 1, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_152594.3:c.70C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689807.1:p.Arg24Ter nonsense NC_000015.10:g.38299410C>T NC_000015.9:g.38591611C>T NG_008980.1:g.51560C>T - Protein change
- R24*
- Other names
- -
- Canonical SPDI
- NC_000015.10:38299409: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
- 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. |
|||
| SPRED1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
827 | 861 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 17, 2023 | RCV000001883.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 1, 2023 | RCV001172084.22 |
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
(Feb 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Legius syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000291524.6
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1810). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1810). This premature translational stop signal has been observed in individuals with Legius syndrome (PMID: 17704776, 19920235, 21089071). This variant is present in population databases (rs121434313, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg24*) in the SPRED1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPRED1 are known to be pathogenic (PMID: 17704776). (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Legius syndrome
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV004013733.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). The variant is predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000001810 / PMID: 17704776). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormality of pulmonary circulation (present) , Right ventricular hypertrophy (present) , Venous thrombosis (present) , Polycythemia (present) , Cafe-au-lait spot (present) , Relative macrocephaly (present) … (more)
Abnormality of pulmonary circulation (present) , Right ventricular hypertrophy (present) , Venous thrombosis (present) , Polycythemia (present) , Cafe-au-lait spot (present) , Relative macrocephaly (present) , Pericardial effusion (present) , Right atrial enlargement (present) (less)
|
|
|
Pathogenic
(Jun 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Legius syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020392.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: SPRED1 c.70C>T (p.Arg24X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly … (more)
Variant summary: SPRED1 c.70C>T (p.Arg24X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251158 control chromosomes (gnomAD). c.70C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) and has been found to segregate with the disease phenotype in at least one family (e.g. Brems_2007). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 17704776). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Legius syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005087183.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 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 Legius syndrome (MIM#611431). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is located within the first 102 nucleotides of the coding sequence and is predicted to escape nonsense-mediated decay). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other 5' NMD-escape variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in several individuals with a neurofibromatosis-like phenotype, cafe-au-lait or Legius syndrome (ClinVar, PMID: 28378438, PMID: 17704776, PMID: 31370276). (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)
|
|
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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: SCV001335022.25
First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024 |
Comment:
SPRED1: PVS1, PP1:Strong, PM2
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Sep 01, 2007)
|
no assertion criteria provided
Method: literature only
|
LEGIUS SYNDROME
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000022039.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2019 |
Comment on evidence:
In affected members of a family with Legius syndrome (LGSS; 611431), Brems et al. (2007) identified a heterozygous 70C-T transition in exon 3 of the … (more)
In affected members of a family with Legius syndrome (LGSS; 611431), Brems et al. (2007) identified a heterozygous 70C-T transition in exon 3 of the SPRED1 gene, resulting in an arg24-to-ter (R24X) substitution. The R24X mutation was present in normal skin and melanocytes from a cafe-au-lait spot of 1 patient, but melanocytes from the cafe-au-lait spot showed an additional somatic SPRED1 mutation. The 2 mutations were located on different alleles, suggesting that SPRED1 function was completely absent in these cells. (less)
|
Comment:
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000001810 / PMID: 17704776). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant summary: SPRED1 c.70C>T (p.Arg24X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251158 control chromosomes (gnomAD). c.70C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) and has been found to segregate with the disease phenotype in at least one family (e.g. Brems_2007). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 17704776). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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 Legius syndrome (MIM#611431). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is located within the first 102 nucleotides of the coding sequence and is predicted to escape nonsense-mediated decay). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other 5' NMD-escape variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in several individuals with a neurofibromatosis-like phenotype, cafe-au-lait or Legius syndrome (ClinVar, PMID: 28378438, PMID: 17704776, PMID: 31370276). (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:
SPRED1: PVS1, PP1:Strong, PM2
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:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1810). This premature translational stop signal has been observed in individuals with Legius syndrome (PMID: 17704776, 19920235, 21089071). This variant is present in population databases (rs121434313, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg24*) in the SPRED1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPRED1 are known to be pathogenic (PMID: 17704776).
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000001810 / PMID: 17704776). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant summary: SPRED1 c.70C>T (p.Arg24X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251158 control chromosomes (gnomAD). c.70C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) and has been found to segregate with the disease phenotype in at least one family (e.g. Brems_2007). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 17704776). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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 Legius syndrome (MIM#611431). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is located within the first 102 nucleotides of the coding sequence and is predicted to escape nonsense-mediated decay). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other 5' NMD-escape variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in several individuals with a neurofibromatosis-like phenotype, cafe-au-lait or Legius syndrome (ClinVar, PMID: 28378438, PMID: 17704776, PMID: 31370276). (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:
SPRED1: PVS1, PP1:Strong, PM2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders. | Giugliano T | Genes | 2019 | PMID: 31370276 |
| Legius syndrome: A case report. | Kimura R | The Journal of dermatology | 2017 | PMID: 28378438 |
| Legius syndrome in fourteen families. | Denayer E | Human mutation | 2011 | PMID: 21089071 |
| Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. | Messiaen L | JAMA | 2009 | PMID: 19920235 |
| Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. | Brems H | Nature genetics | 2007 | PMID: 17704776 |
Text-mined citations for rs121434313 ...
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.