VCV000651833.10 - ClinVar

NC_000002.12:g.(?_165090130)_(166311776_?)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.

(4)

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_000002.12:g.(?_165090130)_(166311776_?)del

Variation ID: 651833 Accession: VCV000651833.10

Type and length

Deletion, 1,221,647 bp

Location

Cytogenetic: 2q24.3 2: 165090130-166311776 (GRCh38) [ NCBI UCSC ] 2: 165946640-167168286 (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	Aug 14, 2019	Nov 11, 2023	Oct 28, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_000002.12:g.(?_165090130)_(166311776_?)del
NC_000002.11:g.(?_165946640)_(167168286_?)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.
SCN1A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2231	4609
SCN2A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2587	2662
CSRNP3		-	-	GRCh38 GRCh37	36	100
GALNT3		-	-	GRCh38 GRCh37	433	496
LOC100506124	-	-	-	GRCh38	-	18
LOC102724058	-	-	-	GRCh38	-	2319
LOC120977013	-	-	-	GRCh38	-	29
LOC126806396	-	-	-	GRCh38	-	18
LOC129388938	-	-	-	GRCh38	-	20
LOC129935043	-	-	-	GRCh38	-	16

There are 9 more genes affected by this variant. See the full set of genes in Variation Viewer (GRCh38 , 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.
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	Oct 28, 2022	RCV000807258.5
Developmental and epileptic encephalopathy, 11 Seizures, benign familial infantile, 3	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV003106069.6
not provided	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV003106068.6
Generalized epilepsy with febrile seizures plus, type 7 Neuropathy, hereditary sensory and autonomic, type 2A	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV003117597.6

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 (Oct 28, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Early infantile epileptic encephalopathy with suppression bursts Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000947301.3 First in ClinVar: Aug 14, 2019 Last updated: Mar 26, 2023	Publications: PubMed (7) PubMed: 17347258‚ 18930999‚ 16865694‚ 17561957‚ 20522430‚ 21719429‚ 26068938 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the SCN1A gene has been identified. Loss-of-function variants in SCN1A are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the SCN1A gene has been identified. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. A similar copy number variant has been observed in individual(s) with Dravet syndrome (PMID: 16865694, 17561957, 20522430, 21719429, 26068938). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 28, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV003791249 appears to (...more) Source: NCBI	Neuropathy, hereditary sensory and autonomic, type 2A Generalized epilepsy with febrile seizures plus, type 7 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003791249.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (4) PubMed: 17470132‚ 19304393‚ 19400878‚ 23662938 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the SCN9A gene has been identified. Loss-of-function variants in SCN9A are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the SCN9A gene has been identified. Loss-of-function variants in SCN9A are known to be pathogenic (PMID: 17470132, 19304393). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of SCN9A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 19400878, 23662938). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 28, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV003791797 appears to (...more) Source: NCBI	Seizures, benign familial infantile, 3 Developmental and epileptic encephalopathy, 11 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003791797.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (3) PubMed: 28379373‚ 19400878‚ 23662938 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the SCN2A gene has been identified. Loss-of-function variants in SCN2A are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the SCN2A gene has been identified. Loss-of-function variants in SCN2A are known to be pathogenic (PMID: 28379373). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of SCN2A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 19400878, 23662938). For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain significance (Oct 28, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV003791578 appears to (...more) Source: NCBI	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003791578.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (1) PubMed: 23662938 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the SCN3A gene has been identified. The current clinical and genetic evidence … (more) A gross deletion of the genomic region encompassing the full coding sequence of the SCN3A gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SCN3A 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. Isolated whole-gene deletions of SCN3A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 23662938). 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)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the SCN1A gene has been identified. Loss-of-function variants in SCN1A are known to be pathogenic (PMID: 17347258, 18930999). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. A similar copy number variant has been observed in individual(s) with Dravet syndrome (PMID: 16865694, 17561957, 20522430, 21719429, 26068938). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the SCN9A gene has been identified. Loss-of-function variants in SCN9A are known to be pathogenic (PMID: 17470132, 19304393). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of SCN9A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 19400878, 23662938). For these reasons, this variant has been classified as Pathogenic.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the SCN2A gene has been identified. Loss-of-function variants in SCN2A are known to be pathogenic (PMID: 28379373). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of SCN2A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 19400878, 23662938). For these reasons, this variant has been classified as Pathogenic.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the SCN3A gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SCN3A 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. Isolated whole-gene deletions of SCN3A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 23662938). 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
Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.	Wolff M	Brain : a journal of neurology	2017	PMID: 28379373
Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy.	Epilepsy Phenome/Genome Project Epi4K Consortium	Annals of neurology	2015	PMID: 26068938
Targeted capture and sequencing for detection of mutations causing early onset epileptic encephalopathy.	Kodera H	Epilepsia	2013	PMID: 23662938
Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology.	Catarino CB	Brain : a journal of neurology	2011	PMID: 21719429
Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome.	Depienne C	Journal of medical genetics	2010	PMID: 20522430
SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis.	Marini C	Epilepsia	2009	PMID: 19400878
Two novel SCN9A mutations causing insensitivity to pain.	Nilsen KB	Pain	2009	PMID: 19304393
Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients.	Depienne C	Journal of medical genetics	2009	PMID: 18930999
Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities.	Marini C	Epilepsia	2007	PMID: 17561957
Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.	Goldberg YP	Clinical genetics	2007	PMID: 17470132
The spectrum of SCN1A-related infantile epileptic encephalopathies.	Harkin LA	Brain : a journal of neurology	2007	PMID: 17347258
Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients.	Suls A	Human mutation	2006	PMID: 16865694
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Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NC_000002.12:g.(?_165090130)_(166311776_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...