Published functional studies demonstrate this variant creates a novel splice acceptor site (SAS), leading to the insertion of seven nucleotides into the RNA sequence, resulting in frameshift and premature truncation of translation (PMID: 18285827); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 24473200, 24176978, 27431290, 18285827, 23829326, 23062754, 27878435, 28600779, 27894351, 31130284, 32552793, 37644014, 33149276)
ClinVar Genomic variation as it relates to human health
NM_022464.5(SIL1):c.1030-9G>A
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
7 out of 8 submissions contributed to this 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
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_022464.5(SIL1):c.1030-9G>A
Variation ID: 280106 Accession: VCV000280106.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q31.2 5: 138947482 (GRCh38) [ NCBI UCSC ] 5: 138283171 (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 Dec 6, 2016 May 15, 2025 Nov 5, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_022464.5:c.1030-9G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001037633.1:c.1030-9G>A NM_001037633.2:c.1030-9G>A intron variant NC_000005.10:g.138947482C>T NC_000005.9:g.138283171C>T NG_008112.2:g.255895G>A - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000005.10:138947481:C:T
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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
Help
The frequency of the allele represented by this VCV record.
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NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00010
- 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. |
|||
| SIL1 | Gene associated with autosomal recessive phenotype | Not yet evaluated |
GRCh38 GRCh37 |
381 | 419 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 5, 2024 | RCV000277678.11 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 30, 2024 | RCV001782768.14 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 7, 2020 | RCV002252076.5 |
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
(Nov 05, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329938.7
First in ClinVar: Dec 06, 2016 Last updated: Feb 16, 2025 |
Comment:
Published functional studies demonstrate this variant creates a novel splice acceptor site (SAS), leading to the insertion of seven nucleotides into the RNA sequence, resulting … (more)
Published functional studies demonstrate this variant creates a novel splice acceptor site (SAS), leading to the insertion of seven nucleotides into the RNA sequence, resulting in frameshift and premature truncation of translation (PMID: 18285827); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 24473200, 24176978, 27431290, 18285827, 23829326, 23062754, 27878435, 28600779, 27894351, 31130284, 32552793, 37644014, 33149276) (less)
|
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Pathogenic
(Sep 29, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000702025.3
First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 1
Zygosity: Homozygote
Sex: mixed
|
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Pathogenic
(Dec 07, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523909.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PM2, PM3
Clinical Features:
Elevated circulating creatine kinase concentration (present)
Geographic origin: Brazil
|
|
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Likely pathogenic
(Jun 15, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Marinesco-Sjögren syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022584.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Mar 17, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: research
|
Marinesco-Sjögren syndrome
Affected status: unknown
Allele origin:
germline
|
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Accession: SCV004805025.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
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Pathogenic
(Oct 30, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Marinesco-Sjögren syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003244158.3
First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025 |
Comment:
This sequence change falls in intron 9 of the SIL1 gene. It does not directly change the encoded amino acid sequence of the SIL1 protein. … (more)
This sequence change falls in intron 9 of the SIL1 gene. It does not directly change the encoded amino acid sequence of the SIL1 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs370290043, gnomAD 0.009%). This variant has been observed in individual(s) with clinical features of Marinesco-Sjogren syndrome (PMID: 24473200, 31130284). ClinVar contains an entry for this variant (Variation ID: 280106). Studies have shown that this variant results in activation of a de novo splice site and introduces a new termination codon (PMID: 32552793). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the SIL1 protein in which other variant(s) (p.Leu373Cysfs*33) have been determined to be pathogenic (internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Likely pathogenic
(Aug 01, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Marinesco-Sjögren syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV006075262.1
First in ClinVar: May 15, 2025 Last updated: May 15, 2025 |
Comment:
PM2 PP5 STRONG
|
|
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Pathogenic
(Apr 01, 2023)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Marinesco-Sjögren syndrome
Affected status: yes
Allele origin:
germline
|
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927905.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
|
Comment:
Comment:
ACMG classification criteria: PS3, PS4, PM2, PM3
Comment:
This sequence change falls in intron 9 of the SIL1 gene. It does not directly change the encoded amino acid sequence of the SIL1 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs370290043, gnomAD 0.009%). This variant has been observed in individual(s) with clinical features of Marinesco-Sjogren syndrome (PMID: 24473200, 31130284). ClinVar contains an entry for this variant (Variation ID: 280106). Studies have shown that this variant results in activation of a de novo splice site and introduces a new termination codon (PMID: 32552793). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the SIL1 protein in which other variant(s) (p.Leu373Cysfs*33) have been determined to be pathogenic (internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
PM2 PP5 STRONG
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 this variant creates a novel splice acceptor site (SAS), leading to the insertion of seven nucleotides into the RNA sequence, resulting in frameshift and premature truncation of translation (PMID: 18285827); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 24473200, 24176978, 27431290, 18285827, 23829326, 23062754, 27878435, 28600779, 27894351, 31130284, 32552793, 37644014, 33149276)
Comment:
ACMG classification criteria: PS3, PS4, PM2, PM3
Comment:
This sequence change falls in intron 9 of the SIL1 gene. It does not directly change the encoded amino acid sequence of the SIL1 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs370290043, gnomAD 0.009%). This variant has been observed in individual(s) with clinical features of Marinesco-Sjogren syndrome (PMID: 24473200, 31130284). ClinVar contains an entry for this variant (Variation ID: 280106). Studies have shown that this variant results in activation of a de novo splice site and introduces a new termination codon (PMID: 32552793). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the SIL1 protein in which other variant(s) (p.Leu373Cysfs*33) have been determined to be pathogenic (internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
PM2 PP5 STRONG
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics. | Maddirevula S | Genome biology | 2020 | PMID: 32552793 |
| Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
| SIL1, a causative cochaperone gene of Marinesco-Söjgren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex. | Inaguma Y | EMBO molecular medicine | 2014 | PMID: 24473200 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SIL1 | - | - | - | - |
Text-mined citations for rs370290043 ...
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 May 17, 2025
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.