VCV001458589.9 - ClinVar

NC_000023.10:g.(?_135067662)_(136652229_?)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.

(3)

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_000023.10:g.(?_135067662)_(136652229_?)del

Variation ID: 1458589 Accession: VCV001458589.9

Type and length

Deletion, 1,584,568 bp

Location

Cytogenetic: Xq26.3 X: 135067662-136652229 (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	Mar 28, 2022	Jun 9, 2024	Apr 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NC_000023.10:g.(?_135067662)_(136652229_?)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.
CD40LG		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	277	457
SLC9A6		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	470	698
ZIC3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	155	325
ARHGEF6		No evidence available	No evidence available	GRCh38 GRCh37	79	259
ADGRG4		-	-	GRCh38 GRCh37	179	354
BRS3		-	-	GRCh38 GRCh37	22	200
FHL1		-	-	GRCh38 GRCh37	495	670
GPR101		-	-	GRCh38 GRCh37	53	230
HTATSF1		-	-	GRCh38 GRCh37	26	204
MAP7D3		-	-	GRCh38 GRCh37	67	245

There are 2 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.
Hyper-IgM syndrome type 1	Pathogenic (1)	criteria provided, single submitter	Jun 27, 2022	RCV001956451.7
Heterotaxy, visceral, 1, X-linked	Pathogenic (1)	criteria provided, single submitter	Apr 21, 2023	RCV001956452.6
Christianson syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 28, 2022	RCV003107929.2

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 (Jun 27, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hyper-IgM syndrome type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002243681.3 First in ClinVar: Mar 28, 2022 Last updated: Nov 11, 2023	Publications: PubMed (3) PubMed: 15319456‚ 15358621‚ 16019685 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the CD40LG gene has been identified. Loss-of-function variants in CD40LG are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the CD40LG gene has been identified. Loss-of-function variants in CD40LG are known to be pathogenic (PMID: 15319456). 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 hyper IgM syndrome (PMID: 15358621, 16019685). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 28, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Christianson syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003791483.1 First in ClinVar: Feb 13, 2023 Last updated: Feb 13, 2023	Publications: PubMed (1) PubMed: 18342287 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the SLC9A6 gene has been identified. Loss-of-function variants in SLC9A6 are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the SLC9A6 gene has been identified. Loss-of-function variants in SLC9A6 are known to be pathogenic (PMID: 18342287). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with SLC9A6-related conditions. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 21, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Heterotaxy, visceral, 1, X-linked Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002238488.4 First in ClinVar: Mar 28, 2022 Last updated: Jun 09, 2024	Publications: PubMed (2) PubMed: 21465648‚ 24123890 Comment: For these reasons, this variant has been classified as Pathogenic. A similar copy number variant has been observed in individual(s) with ZIC3-related conditions (PMID: 21465648). … (more) For these reasons, this variant has been classified as Pathogenic. A similar copy number variant has been observed in individual(s) with ZIC3-related conditions (PMID: 21465648). A gross deletion of the genomic region encompassing the full coding sequence of the ZIC3 gene has been identified. Loss-of-function variants in ZIC3 are known to be pathogenic (PMID: 24123890). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. (less)

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the CD40LG gene has been identified. Loss-of-function variants in CD40LG are known to be pathogenic (PMID: 15319456). 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 hyper IgM syndrome (PMID: 15358621, 16019685). 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 SLC9A6 gene has been identified. Loss-of-function variants in SLC9A6 are known to be pathogenic (PMID: 18342287). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with SLC9A6-related conditions. For these reasons, this variant has been classified as Pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. A similar copy number variant has been observed in individual(s) with ZIC3-related conditions (PMID: 21465648). A gross deletion of the genomic region encompassing the full coding sequence of the ZIC3 gene has been identified. Loss-of-function variants in ZIC3 are known to be pathogenic (PMID: 24123890). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes.

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 functional analyses of ZIC3 variants in congenital heart disease.	Cowan J	Human mutation	2014	PMID: 24123890
From VACTERL-H to heterotaxy: variable expressivity of ZIC3-related disorders.	Chung B	American journal of medical genetics. Part A	2011	PMID: 21465648
SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.	Gilfillan GD	American journal of human genetics	2008	PMID: 18342287
Autoimmune retinopathy with RPE hypersensitivity and 'negative ERG' in X-linked hyper-IgM syndrome.	Schuster A	Ocular immunology and inflammation	2005	PMID: 16019685
Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome.	Lee WI	Blood	2005	PMID: 15358621
The hyper IgM syndrome--an evolving story.	Etzioni A	Pediatric research	2004	PMID: 15319456

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NC_000023.10:g.(?_135067662)_(136652229_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...