ClinVar Genomic variation as it relates to human health
NM_014846.4(WASHC5):c.1876G>T (p.Val626Phe)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014846.4(WASHC5):c.1876G>T (p.Val626Phe)
Variation ID: 1161 Accession: VCV000001161.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q24.13 8: 125056817 (GRCh38) [ NCBI UCSC ] 8: 126069059 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 May 1, 2024 Apr 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014846.4:c.1876G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055661.3:p.Val626Phe missense NM_001330609.2:c.1432G>T NP_001317538.1:p.Val478Phe missense NC_000008.11:g.125056817C>A NC_000008.10:g.126069059C>A NG_012636.1:g.40003G>T Q12768:p.Val626Phe - Protein change
- V626F, V478F
- Other names
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- Canonical SPDI
- NC_000008.11:125056816:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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WASHC5 | - | - |
GRCh38 GRCh37 |
557 | 707 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2023 | RCV000001220.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 19, 2020 | RCV002227984.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2021 | RCV001847561.11 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 13, 2023 | RCV003320543.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003242958.9 |
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
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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
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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
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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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Likely pathogenic
(Oct 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002104786.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
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Pathogenic
(Dec 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Ritscher-Schinzel syndrome
Hereditary spastic paraplegia 8
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000550574.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies with zebrafish knockdowns showed that a WASHC5 protein with this variant failed to … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies with zebrafish knockdowns showed that a WASHC5 protein with this variant failed to rescue disease phenotype, suggesting that this variant functionally impairs the WASHC5 protein (PMID: 17160902). This variant has been reported to segregate with disease in three families affected with hereditary spastic paraplegia (PMID: 17160902). This gene is also known as KIAA0196 and/or strumpellin in the literature. ClinVar contains an entry for this variant (Variation ID: 1161). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 626 of the WASHC5 protein (p.Val626Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. (less)
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003965445.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The c.1876G>T (p.V626F) alteration is located in exon 16 (coding exon 15) of the WASHC5 gene. This alteration results from a G to T substitution … (more)
The c.1876G>T (p.V626F) alteration is located in exon 16 (coding exon 15) of the WASHC5 gene. This alteration results from a G to T substitution at nucleotide position 1876, causing the valine (V) at amino acid position 626 to be replaced by a phenylalanine (F). This variant impacts the first base pair of coding exon 15. This variant is expected to be causative of WASHC5-related spastic paraplegia; however, its clinical significance for Ritscher-Schinzel syndrome is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been previously reported in the heterozygous state in multiple individuals with hereditary spastic paraplegia (Valdmanis, 2007). This amino acid position is highly conserved in available vertebrate species. Functional evidence suggests that p.V626F impacts protein function and CAV1-dependent, integrin-mediated cell adhesion; however, the physiological relevance of these findings is unclear (Valdmanis, 2007; Freeman, 2013; Lee, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 8
Affected status: yes
Allele origin:
unknown
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Paris Brain Institute, Inserm - ICM
Accession: SCV001451200.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 2
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Likely pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 8
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841411.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001161). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hyperreflexia (present) , Lower limb muscle weakness (present) , Involuntary movements (present)
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Likely pathogenic
(Feb 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV004025823.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
Published functional studies demonstrate discrepant effects of this variant on endosomal tubulation (Freeman et al., 2013; Lee et al., 2020) and protein interactions (Valdmanis et … (more)
Published functional studies demonstrate discrepant effects of this variant on endosomal tubulation (Freeman et al., 2013; Lee et al., 2020) and protein interactions (Valdmanis et al., 2007; Huttlin et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34184482, 25525159, 30072228, 24451228, 23881105, 35667337, 26659599, 26147798, 28569743, 28514442, 31911435, 26973516, 17160902, 28181327, 20301727, 34312900, 30061306, 23085491) (less)
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Pathogenic
(Oct 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV004229213.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
This variant segregates with spastic paraplegia in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence … (more)
This variant segregates with spastic paraplegia in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 17160902, 31911435. (less)
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Pathogenic
(Jan 01, 2007)
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no assertion criteria provided
Method: literature only
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SPASTIC PARAPLEGIA 8, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021370.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2019 |
Comment on evidence:
In 4 apparently unrelated families of European ancestry, Valdmanis et al. (2007) found that a val626-to-phe (V626F) mutation in the KIAA0196 gene, arising from a … (more)
In 4 apparently unrelated families of European ancestry, Valdmanis et al. (2007) found that a val626-to-phe (V626F) mutation in the KIAA0196 gene, arising from a heterozygous 1956G-T transversion in exon 15, segregated with spastic paraplegia (SPG8; 603563). (less)
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not provided
(-)
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no classification provided
Method: literature only
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Hereditary spastic paraplegia 8
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000041272.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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[Autosomal dominant spastic paraplegias]. | Rudenskaya GE | Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova | 2021 | PMID: 34184482 |
Hereditary spastic paraplegia SPG8 mutations impair CAV1-dependent, integrin-mediated cell adhesion. | Lee S | Science signaling | 2020 | PMID: 31911435 |
Spastic Paraplegia 8. | Adam MP | - | 2020 | PMID: 20301727 |
Architecture of the human interactome defines protein communities and disease networks. | Huttlin EL | Nature | 2017 | PMID: 28514442 |
The hereditary spastic paraplegia protein strumpellin: characterisation in neurons and of the effect of disease mutations on WASH complex assembly and function. | Freeman C | Biochimica et biophysica acta | 2013 | PMID: 23085491 |
Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases. | Clemen CS | Brain : a journal of neurology | 2010 | PMID: 20833645 |
Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. | Valdmanis PN | American journal of human genetics | 2007 | PMID: 17160902 |
Text-mined citations for rs80338867 ...
HelpRecord last updated May 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.