VCV003243458.1 - ClinVar

NC_000016.9:g.(?_2104449)_(2286921_?)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.

(1)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000016.9:g.(?_2104449)_(2286921_?)del

Variation ID: 3243458 Accession: VCV003243458.1

Type and length

Deletion, 182,473 bp

Location

Cytogenetic: 16p13.3 16: 2104449-2286921 (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 17, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NC_000016.9:g.(?_2104449)_(2286921_?)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.
PKD1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	3777	4362
TSC2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	10758	10957
BRICD5	-	-	-	GRCh38 GRCh37	25	82
CASKIN1		-	-	GRCh38 GRCh37	134	185
DNASE1L2		-	-	GRCh38 GRCh37	14	59
E4F1		-	-	GRCh38 GRCh37	64	115
MIR1225		-	-	GRCh38 GRCh37	-	107
MLST8		-	-	GRCh38 GRCh37	14	71
PGP		-	-	GRCh38 GRCh37	12	65
RAB26		-	-	GRCh38 GRCh37	32	83

There is 1 more gene 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.
Tuberous sclerosis 2	Pathogenic (1)	criteria provided, single submitter	Jul 17, 2018	RCV004582686.2

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 17, 2018)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Tuberous sclerosis 2 Affected status: unknown Allele origin: unknown	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV005062276.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Publications: PubMed (4) PubMed: 17287951‚ 11112665‚ 21520333‚ 27406250 Comment: For these reasons, this variant has been classified as Pathogenic. Smaller in-frame deletions (e11 deletion and e11-e12 deletion, also knows as e10 deletion and e10-e11 … (more) For these reasons, this variant has been classified as Pathogenic. Smaller in-frame deletions (e11 deletion and e11-e12 deletion, also knows as e10 deletion and e10-e11 deletion in the literature) that are fully encompassed by this deletion have been reported in individuals affected with tuberous sclerosis complex and have been determined to be pathogenic (PMID: 17287951, 11112665, 21520333).¬†This suggests that deletion of this region of the TSC2 protein is causative of disease. Similar deletions of exons 6-42 have been observed in individuals affected with tuberous sclerosis complex (PMID: 27406250, Invitae). This variant is a gross deletion of the genomic region encompassing exons 6-42 of the TSC2 gene. The 5' boundary is likely confined to intron 4. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Smaller in-frame deletions (e11 deletion and e11-e12 deletion, also knows as e10 deletion and e10-e11 deletion in the literature) that are fully encompassed by this deletion have been reported in individuals affected with tuberous sclerosis complex and have been determined to be pathogenic (PMID: 17287951, 11112665, 21520333).¬†This suggests that deletion of this region of the TSC2 protein is causative of disease. Similar deletions of exons 6-42 have been observed in individuals affected with tuberous sclerosis complex (PMID: 27406250, Invitae). This variant is a gross deletion of the genomic region encompassing exons 6-42 of the TSC2 gene. The 5' boundary is likely confined to intron 4. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation.

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
Genotype and brain pathology phenotype in children with tuberous sclerosis complex.	Overwater IE	European journal of human genetics : EJHG	2016	PMID: 27406250
LOVD v.2.0: the next generation in gene variant databases.	Fokkema IF	Human mutation	2011	PMID: 21520333
Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations.	Kozlowski P	Human genetics	2007	PMID: 17287951
Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.	Dabora SL	American journal of human genetics	2001	PMID: 11112665

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NC_000016.9:g.(?_2104449)_(2286921_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...