VCV000008025.2 - ClinVar

NM_003073.5(SMARCB1):c.986+1G>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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003073.5(SMARCB1):c.986+1G>A

Variation ID: 8025 Accession: VCV000008025.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q11.23 22: 23825416 (GRCh38) [ NCBI UCSC ] 22: 24167603 (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	Jan 20, 2018	May 1, 2024	Nov 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003073.5:c.986+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001007468.3:c.959+1G>A		splice donor
NM_001317946.2:c.1013+1G>A		splice donor
NM_001362877.2:c.1040+1G>A		splice donor
NC_000022.11:g.23825416G>A
NC_000022.10:g.24167603G>A
NG_009303.1:g.43454G>A
NG_145148.1:g.300G>A
LRG_520:g.43454G>A
LRG_520t1:c.986+1G>A

... more HGVS ... less HGVS

Protein change

Other names

IVS7DS, G-A, +1

Canonical SPDI

NC_000022.11:23825415:G:A

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

OMIM: 601607.0004 dbSNP: rs112038099 VarSome

Comment on variant

ClinGen staff contributed the HGVS expression for this variant.

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.
SMARCB1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	1072	1211

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.
Rhabdoid tumor predisposition syndrome 1	Pathogenic (1)	no assertion criteria provided	Apr 1, 2000	RCV000008489.3
Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	Nov 20, 2023	RCV004018590.1

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.
Likely pathogenic (Nov 20, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005020284.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: The c.986+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 7 of the SMARCB1 gene. Alterations that disrupt the … (more) The c.986+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 7 of the SMARCB1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Loss-of-function variants in SMARCB1 are known to cause rhabdoid tumor predisposition syndrome; however, such associations with neurodevelopmental disorders are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Eaton KW et al. Pediatr Blood Cancer. 2011 Jan;56(1):7-15). Based on the supporting evidence, this alteration is likely pathogenic for SMARCB1-related tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unknown. (less)
Pathogenic (Apr 01, 2000)	no assertion criteria provided Method: literature only	RHABDOID TUMOR PREDISPOSITION SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028697.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 20, 2018	Publications: PubMed (1) PubMed: 10739763 Comment on evidence: Taylor et al. (2000) identified a family afflicted over multiple generations with posterior fossa tumors of infancy, including central nervous system malignant rhabdoid tumor and … (more) Taylor et al. (2000) identified a family afflicted over multiple generations with posterior fossa tumors of infancy, including central nervous system malignant rhabdoid tumor and choroid plexus carcinoma, consistent with the rhabdoid tumor predisposition syndrome-1 (RTPS1; 609322). Both affected and some unaffected family members had a germline splice site mutation of the SMARCB1 gene, leading to exclusion of exon 7 from the mature cDNA and a subsequent frameshift. Tumor tissue showed loss of the wildtype SMARCB1 allele, in keeping with a tumor suppressor gene. The findings suggested that germline mutations in SMARCB1 are associated with a novel autosomal dominant syndrome with incomplete penetrance that predisposes to malignant posterior fossa brain tumors of infancy. (less)

Comment:

The c.986+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 7 of the SMARCB1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Loss-of-function variants in SMARCB1 are known to cause rhabdoid tumor predisposition syndrome; however, such associations with neurodevelopmental disorders are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Eaton KW et al. Pediatr Blood Cancer. 2011 Jan;56(1):7-15). Based on the supporting evidence, this alteration is likely pathogenic for SMARCB1-related tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unknown.

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
Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene.	Taylor MD	American journal of human genetics	2000	PMID: 10739763

Text-mined citations for rs112038099 ...

These 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 01, 2024

ClinVar Genomic variation as it relates to human health

NM_003073.5(SMARCB1):c.986+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs112038099 ...