Published functional studies demonstrate protein retention in the endoplasmic reticulum as well as inability to bind beta-glucocerebrosidase (Blanz et al., 2010); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29941711, 15364701, 24389070, 23659519, 22884962, 29655203, 19933215, 18308289)
ClinVar Genomic variation as it relates to human health
NM_005506.4(SCARB2):c.434_435dup (p.Trp146fs)
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_005506.4(SCARB2):c.434_435dup (p.Trp146fs)
Variation ID: 7377 Accession: VCV000007377.19
- Type and length
-
Microsatellite, 2 bp
- Location
-
Cytogenetic: 4q21.1 4: 76179693-76179694 (GRCh38) [ NCBI UCSC ] 4: 77100846-77100847 (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 Aug 7, 2015 May 1, 2024 Jan 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005506.4:c.434_435dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005497.1:p.Trp146fs frameshift NM_001204255.2:c.276-3787AG[3] intron variant NM_005506.3:c.434_435dup NC_000004.12:g.76179694CT[3] NC_000004.11:g.77100847CT[3] NG_012054.1:g.39186AG[3] - Protein change
- W146fs
- Other names
- -
- Canonical SPDI
- NC_000004.12:76179693:CTCT:CTCTCT
-
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.
- -
- 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. |
|||
| SCARB2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
488 | 517 | |
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
|
Apr 6, 2022 | RCV000007802.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 6, 2022 | RCV000188810.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 5, 2024 | RCV001203979.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 28, 2017 | RCV002326669.2 |
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
(Apr 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Action myoclonus-renal failure syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002797419.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000242434.7
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate protein retention in the endoplasmic reticulum as well as inability to bind beta-glucocerebrosidase (Blanz et al., 2010); Frameshift variant predicted to … (more)
Published functional studies demonstrate protein retention in the endoplasmic reticulum as well as inability to bind beta-glucocerebrosidase (Blanz et al., 2010); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29941711, 15364701, 24389070, 23659519, 22884962, 29655203, 19933215, 18308289) (less)
|
|
|
Pathogenic
(Mar 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Action myoclonus-renal failure syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019998.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive myoclonic epilepsy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001375164.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp146Serfs*16) 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.Trp146Serfs*16) 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 (rs727502773, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with SCARB2-related conditions (PMID: 18308289). This variant is also known as c.435_436insAG. ClinVar contains an entry for this variant (Variation ID: 7377). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002631019.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.434_435dupAG pathogenic mutation, located in coding exon 4 of the SCARB2 gene, results from a duplication of AG at nucleotide position 434, causing a … (more)
The c.434_435dupAG pathogenic mutation, located in coding exon 4 of the SCARB2 gene, results from a duplication of AG at nucleotide position 434, causing a translational frameshift with a predicted alternate stop codon (p.W146Sfs*16). This mutation was first reported in a homozygous individual with action myoclonus-renal failure syndrome (Berkovic SF et al. Am. J. Hum. Genet., 2008 Mar;82:673-84). It was also detected in conjuction with a second SCARB2 alteration in a 22-year-old female with steroid resistant nephrotic syndrome, tremor and ataxia, suspected action myoclonus-renal failure syndrome, and focal segmental glomerulosclerosis on biopsy; however, the phase of the alterations was not provided (Sen ES et al. J. Med. Genet., 2017 Aug; doi: 10.1136/jmedgenet-2017-104811). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Mar 01, 2008)
|
no assertion criteria provided
Method: literature only
|
EPILEPSY, PROGRESSIVE MYOCLONIC, 4, WITH RENAL FAILURE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028003.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 25, 2018 |
Comment on evidence:
In an Australian woman whose ancestors came from Britain and who had no known consanguineous ancestry, Berkovic et al. (2008) found a frameshift mutation in … (more)
In an Australian woman whose ancestors came from Britain and who had no known consanguineous ancestry, Berkovic et al. (2008) found a frameshift mutation in exon 4 of the SCARB2 gene, 435_436insAG, as the cause of progressive myoclonic epilepsy-4 with renal failure (EPM4; 254900). The mutation resulted in frameshift predicted to truncate the protein to 160 amino acids (Trp146SerfsTer16). Berkovic et al. (2008) found the same mutation in a Canadian case without French Canadian ancestry reported by Badhwar et al. (2004). Parental DNA was not available for testing, so Berkovic et al. (2008) were unable to distinguish whether the mutation was homozygous or hemizygous for deletion of a segment of the chromosome 4 homolog that would normally bear the second pathogenic allele. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Action myoclonus-renal failure syndrome
Affected status: unknown
Allele origin:
paternal
|
GenomeConnect, ClinGen
Accession: SCV002074943.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Comment:
Variant interpreted as Pathogenic and reported on 04-23-2020 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 04-23-2020 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Tinnitus (present) , Vertigo (present) , Movement disorder (present) , Atrophic scars (present) , Hyperextensible skin (present) , Abnormal curvature of the vertebral column (present) … (more)
Tinnitus (present) , Vertigo (present) , Movement disorder (present) , Atrophic scars (present) , Hyperextensible skin (present) , Abnormal curvature of the vertebral column (present) , Joint hypermobility (present) , Tooth malposition (present) (less)
Indication for testing: Diagnostic
Age: 40-49 years
Sex: male
Testing laboratory: PreventionGenetics,PreventionGenetics
Date variant was reported to submitter: 2020-04-23
Testing laboratory interpretation: Pathogenic
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Action myoclonus-renal failure syndrome
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000328630.2
First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Trp146Serfs*16) 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 (rs727502773, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with SCARB2-related conditions (PMID: 18308289). This variant is also known as c.435_436insAG. ClinVar contains an entry for this variant (Variation ID: 7377). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.434_435dupAG pathogenic mutation, located in coding exon 4 of the SCARB2 gene, results from a duplication of AG at nucleotide position 434, causing a translational frameshift with a predicted alternate stop codon (p.W146Sfs*16). This mutation was first reported in a homozygous individual with action myoclonus-renal failure syndrome (Berkovic SF et al. Am. J. Hum. Genet., 2008 Mar;82:673-84). It was also detected in conjuction with a second SCARB2 alteration in a 22-year-old female with steroid resistant nephrotic syndrome, tremor and ataxia, suspected action myoclonus-renal failure syndrome, and focal segmental glomerulosclerosis on biopsy; however, the phase of the alterations was not provided (Sen ES et al. J. Med. Genet., 2017 Aug; doi: 10.1136/jmedgenet-2017-104811). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Variant interpreted as Pathogenic and reported on 04-23-2020 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
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 protein retention in the endoplasmic reticulum as well as inability to bind beta-glucocerebrosidase (Blanz et al., 2010); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29941711, 15364701, 24389070, 23659519, 22884962, 29655203, 19933215, 18308289)
Comment:
This sequence change creates a premature translational stop signal (p.Trp146Serfs*16) 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 (rs727502773, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with SCARB2-related conditions (PMID: 18308289). This variant is also known as c.435_436insAG. ClinVar contains an entry for this variant (Variation ID: 7377). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.434_435dupAG pathogenic mutation, located in coding exon 4 of the SCARB2 gene, results from a duplication of AG at nucleotide position 434, causing a translational frameshift with a predicted alternate stop codon (p.W146Sfs*16). This mutation was first reported in a homozygous individual with action myoclonus-renal failure syndrome (Berkovic SF et al. Am. J. Hum. Genet., 2008 Mar;82:673-84). It was also detected in conjuction with a second SCARB2 alteration in a 22-year-old female with steroid resistant nephrotic syndrome, tremor and ataxia, suspected action myoclonus-renal failure syndrome, and focal segmental glomerulosclerosis on biopsy; however, the phase of the alterations was not provided (Sen ES et al. J. Med. Genet., 2017 Aug; doi: 10.1136/jmedgenet-2017-104811). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Variant interpreted as Pathogenic and reported on 04-23-2020 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| SCARB2-Related Action Myoclonus – Renal Failure Syndrome. | Adam MP | - | 2023 | PMID: 26677510 |
| Clinical genetic testing using a custom-designed steroid-resistant nephrotic syndrome gene panel: analysis and recommendations. | Sen ES | Journal of medical genetics | 2017 | PMID: 28780565 |
| 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 |
| 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 rs727502773 ...
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 Sep 29, 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.