ClinVar Genomic variation as it relates to human health
NM_005506.4(SCARB2):c.862C>T (p.Gln288Ter)
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_005506.4(SCARB2):c.862C>T (p.Gln288Ter)
Variation ID: 7378 Accession: VCV000007378.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q21.1 4: 76174276 (GRCh38) [ NCBI UCSC ] 4: 77095429 (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 Jan 23, 2015 Feb 14, 2024 Dec 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005506.4:c.862C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005497.1:p.Gln288Ter nonsense NM_001204255.2:c.433C>T NP_001191184.1:p.Gln145Ter nonsense NC_000004.12:g.76174276G>A NC_000004.11:g.77095429G>A NG_012054.1:g.44607C>T - Protein change
- Q288*, Q145*
- Other names
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- Canonical SPDI
- NC_000004.12:76174275:G: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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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SCARB2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
487 | 516 |
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
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Oct 26, 2023 | RCV000007803.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 17, 2017 | RCV000488955.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV001390386.15 |
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
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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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Pathogenic
(Mar 17, 2017)
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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: SCV000577552.4
First in ClinVar: May 22, 2017 Last updated: May 22, 2017 |
Comment:
The Q288X nonsense variant in the SCARB2 gene has been reported previously in association with action myoclonus-renal failure syndrome and also progressive myoclonic epilepsy without … (more)
The Q288X nonsense variant in the SCARB2 gene has been reported previously in association with action myoclonus-renal failure syndrome and also progressive myoclonic epilepsy without renal failure (Berkovic et al., 2008; Dibbens et al., 2011). Functional analysis shows that Q288X disrupts the normal trafficking of the SCARB2 protein (Blanz et al., 2010). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, it was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, Q288X is interpreted to be a pathogenic variant. (less)
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Pathogenic
(Mar 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Action myoclonus-renal failure syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002813619.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Action myoclonus-renal failure syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122208.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: SCARB2 c.862C>T (p.Gln288X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: SCARB2 c.862C>T (p.Gln288X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 4e-06 in 251182 control chromosomes (gnomAD). c.862C>T has been reported in the literature in individuals affected with features of Action Myoclonus-Renal Failure Syndrome (examples: Berkovic_2008, and Li_2023). At least one publication reports experimental evidence that this variant disrupts the normal trafficking of the SCARB2 protein (Blanz_2010). The following publications have been ascertained in the context of this evaluation (PMID: 18308289, 19933215, 35478072). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive myoclonic epilepsy
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001592099.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln288*) in the SCARB2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln288*) in the SCARB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCARB2 are known to be pathogenic (PMID: 19847901). This variant is present in population databases (rs121909118, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of SCARB2-related conditions (PMID: 18308289). ClinVar contains an entry for this variant (Variation ID: 7378). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2011)
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no assertion criteria provided
Method: literature only
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EPILEPSY, PROGRESSIVE MYOCLONIC, 4, WITH OR WITHOUT RENAL FAILURE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028004.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 23, 2015 |
Comment on evidence:
Berkovic et al. (2008) identified an SCARB2 mutation in 1 of the original families with action myoclonus with renal failure (EPM4; 254900) from Quebec reported … (more)
Berkovic et al. (2008) identified an SCARB2 mutation in 1 of the original families with action myoclonus with renal failure (EPM4; 254900) from Quebec reported by Badhwar et al. (2004). The 3 affected members were deceased, and no DNA was available for testing, but obligate carriers of this disorder had the mutation in exon 7 862C-T (gln288ter, Q288X), which was predicted to terminate the protein prematurely or lead to nonsense-mediated RNA decay of the transcript. In a patient with progressive myoclonic epilepsy without renal failure, Dibbens et al. (2011) identified compound heterozygosity for 2 mutations in the SCARB2 gene: Q288X and a 1-bp insertion in intron 9 (1187+3insT; 602257.0007). The patient was originally reported by Costello et al. (2009). He had onset of myoclonic epilepsy at age 16 years, and became severely disabled, requiring a wheelchair by age 20. At age 27, he had intractable myoclonus, dysarthria, and dysphagia, but cognition remained intact and there was no evidence of renal failure. Electrophysiologic studies indicated a demyelinating peripheral neuropathy, with reduced sensory and motor action potentials and mildly decreased nerve conduction velocities. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Action myoclonus-renal failure syndrome
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000328636.2
First in ClinVar: Oct 11, 2015 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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Usage of Genetic Panels in an Adult Epilepsy Clinic. | Li J | The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques | 2023 | PMID: 35478072 |
SCARB2-Related Action Myoclonus – Renal Failure Syndrome. | Adam MP | - | 2023 | PMID: 26677510 |
Mutation of SCARB2 in a patient with progressive myoclonus epilepsy and demyelinating peripheral neuropathy. | Dibbens LM | Archives of neurology | 2011 | PMID: 21670406 |
Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand beta-glucocerebrosidase. | Blanz J | Human molecular genetics | 2010 | PMID: 19933215 |
SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure. | Dibbens LM | Annals of neurology | 2009 | PMID: 19847901 |
Progressive myoclonus epilepsy with demyelinating peripheral neuropathy and preserved intellect: a novel syndrome. | Costello DJ | Archives of neurology | 2009 | PMID: 19597094 |
Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. | Berkovic SF | American journal of human genetics | 2008 | PMID: 18308289 |
Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder. | Badhwar A | Brain : a journal of neurology | 2004 | PMID: 15364701 |
Text-mined citations for rs121909118 ...
HelpRecord last updated Oct 13, 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.