VCV002136336.3 - ClinVar

NM_022464.5(SIL1):c.1030-18G>A

Germline

Classification

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.

(2)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022464.5(SIL1):c.1030-18G>A

Variation ID: 2136336 Accession: VCV002136336.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q31.2 5: 138947491 (GRCh38) [ NCBI UCSC ] 5: 138283180 (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	Feb 8, 2023	Feb 14, 2024	Feb 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_022464.5:c.1030-18G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001037633.2:c.1030-18G>A		intron variant
NC_000005.10:g.138947491C>T
NC_000005.9:g.138283180C>T
NG_008112.2:g.255886G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000005.10:138947490:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

VarSome

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
Gene	OMIM	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		-	-	GRCh38 GRCh37	354	392

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.
Marinesco-Sjögren syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Feb 23, 2023	RCV003060014.5

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.
Uncertain significance (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Marinesco-Sjögren syndrome Affected status: yes Allele origin: unknown	3billion Accession: SCV003841628.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: This intron variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tools predict the variant … (more) This intron variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.99). This variant is classified as VUS according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Cerebellar ataxia (present) , Cataract (present) , Dysarthria (present) , Movement disorder (present)
Pathogenic (May 07, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Marinesco-Sjögren syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003439236.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 16282977 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 (rs769052639, gnomAD 0.003%). This variant has been observed in individual(s) with Marinesco-Sjogren syndrome (PMID: 16282977). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. Studies have shown that this variant results in activation of a cryptic splice site in intron 9 and inclusion of 16 nucleotides in the mature transcript and introduces a new termination codon (PMID: 16282977). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This intron variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.99). This variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

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 (rs769052639, gnomAD 0.003%). This variant has been observed in individual(s) with Marinesco-Sjogren syndrome (PMID: 16282977). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. Studies have shown that this variant results in activation of a cryptic splice site in intron 9 and inclusion of 16 nucleotides in the mature transcript and introduces a new termination codon (PMID: 16282977). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy.	Senderek J	Nature genetics	2005	PMID: 16282977

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_022464.5(SIL1):c.1030-18G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...