VCV003248150.1 - ClinVar

NC_000021.8:g.(?_44473990)_(45629566_?)del

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

NC_000021.8:g.(?_44473990)_(45629566_?)del

Variation ID: 3248150 Accession: VCV003248150.1

Type and length

Deletion, 1,155,577 bp

Location

Cytogenetic: 21q22.3 21: 44473990-45629566 (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	Jun 30, 2024	Jun 29, 2024	Jul 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NC_000021.8:g.(?_44473990)_(45629566_?)del

Protein change

Other names

Canonical SPDI

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.
TRAPPC10		No evidence available	No evidence available	GRCh38 GRCh37	85	197
AGPAT3		-	-	GRCh38 GRCh37	19	121
CBS		-	-	GRCh38 GRCh37	1287	1382
CRYAA		-	-	GRCh38 GRCh37	89	186
CSTB		-	-	GRCh38 GRCh37	113	281
GATD3		-	-	GRCh38 GRCh37	6	113
HSF2BP		-	-	GRCh38 GRCh37	26	137
PDXK		-	-	GRCh38 GRCh37	53	165
PWP2		-	-	GRCh38 GRCh37	73	184
RRP1		-	-	GRCh38 GRCh37	48	155

There are 3 more genes affected by this variant. See the full set of genes in Variation Viewer (GRCh37) and ClinGen Dosage Sensitivity Map.

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.
Progressive myoclonic epilepsy	Pathogenic (1)	criteria provided, single submitter	Jul 12, 2023	RCV004579317.2
Developmental and epileptic encephalopathy, 30	Uncertain significance (1)	criteria provided, single submitter	Jul 12, 2023	RCV004579318.2

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 (Jul 12, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Progressive myoclonic epilepsy Affected status: unknown Allele origin: unknown	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV005068067.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Publications: PubMed (1) PubMed: 8596935 Comment: For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with CSTB-related conditions. … (more) For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with CSTB-related conditions. A gross deletion of the genomic region encompassing the full coding sequence of the CSTB gene has been identified. Loss-of-function variants in CSTB are known to be pathogenic (PMID: 8596935). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. (less)
Uncertain significance (Jul 12, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Developmental and epileptic encephalopathy, 30 Affected status: unknown Allele origin: unknown	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV005068083.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Comment: This variant has not been reported in the literature in individuals affected with SIK1-related conditions. A gross deletion of the genomic region encompassing the full … (more) This variant has not been reported in the literature in individuals affected with SIK1-related conditions. A gross deletion of the genomic region encompassing the full coding sequence of the SIK1 gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SIK1 cause disease. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with CSTB-related conditions. A gross deletion of the genomic region encompassing the full coding sequence of the CSTB gene has been identified. Loss-of-function variants in CSTB are known to be pathogenic (PMID: 8596935). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes.

Comment:

This variant has not been reported in the literature in individuals affected with SIK1-related conditions. A gross deletion of the genomic region encompassing the full coding sequence of the SIK1 gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SIK1 cause disease. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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 the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1).	Pennacchio LA	Science (New York, N.Y.)	1996	PMID: 8596935

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NC_000021.8:g.(?_44473990)_(45629566_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...