VCV002424811.3 - ClinVar

NC_000013.10:g.(?_20797176)_(21105944_?)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_000013.10:g.(?_20797176)_(21105944_?)del

Variation ID: 2424811 Accession: VCV002424811.3

Type and length

Deletion, 308,769 bp

Location

Cytogenetic: 13q12.11 13: 20797176-21105944 (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	Feb 13, 2023	Jun 9, 2024	Jan 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NC_000013.10:g.(?_20797176)_(21105944_?)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.
GJB2		Dosage sensitivity unlikely	No evidence available	GRCh38 GRCh37	570	637
GJB6		No evidence available	No evidence available	GRCh38 GRCh37	195	279
CRYL1		-	-	GRCh38 GRCh37	106	203

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 22, 2024	RCV003107795.5

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 (Jan 22, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003792560.2 First in ClinVar: Feb 13, 2023 Last updated: Jun 09, 2024	Publications: PubMed (6) PubMed: 11807148‚ 14759569‚ 32067424‚ 31586237‚ 19723508‚ 17227867 Comment: This variant occurs in a non-coding region of the GJB2 gene and encompasses exon(s) 1-2 and part of exon 3 (c.-301125_444del) of the GJB6 gene. … (more) This variant occurs in a non-coding region of the GJB2 gene and encompasses exon(s) 1-2 and part of exon 3 (c.-301125_444del) of the GJB6 gene. It does not change the encoded amino acid sequence of the GJB2 protein. A similar copy number variant encompassing part of GJB6 in addition to upstream sequence containing regulatory elements that impact GJB2 expression, commonly known as ‚àÜGJB6-D13S1830, has been observed homozygous or in trans with a pathogenic variant in the adjacent GJB2 gene in individual(s) with non-syndromic deafness (PMID: 11807148, 14759569, 32067424, 31586237). It has also been observed to segregate with disease in related individuals. Deletions overlapping the GJB6 gene and upstream regulatory regions have been shown to impact expression of the GJB2 allele (PMID: 19723508, 17227867). For these reasons, this variant has been classified as Pathogenic for GJB2-related conditions, either in homozygosity or in trans with another pathogenic variant in GJB2. (less)

Comment:

This variant occurs in a non-coding region of the GJB2 gene and encompasses exon(s) 1-2 and part of exon 3 (c.-301125_444del) of the GJB6 gene. It does not change the encoded amino acid sequence of the GJB2 protein. A similar copy number variant encompassing part of GJB6 in addition to upstream sequence containing regulatory elements that impact GJB2 expression, commonly known as ‚àÜGJB6-D13S1830, has been observed homozygous or in trans with a pathogenic variant in the adjacent GJB2 gene in individual(s) with non-syndromic deafness (PMID: 11807148, 14759569, 32067424, 31586237). It has also been observed to segregate with disease in related individuals. Deletions overlapping the GJB6 gene and upstream regulatory regions have been shown to impact expression of the GJB2 allele (PMID: 19723508, 17227867). For these reasons, this variant has been classified as Pathogenic for GJB2-related conditions, either in homozygosity or in trans with another pathogenic variant in GJB2.

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
Analyses of del(GJB6-D13S1830) and del(GJB6-D13S1834) deletions in a large cohort with hearing loss: Caveats to interpretation of molecular test results in multiplex families.	Pandya A	Molecular genetics & genomic medicine	2020	PMID: 32067424
Characterization of GJB2 cis-regulatory elements in the DFNB1 locus.	Moisan S	Human genetics	2019	PMID: 31586237
The digenic hypothesis unraveled: the GJB6 del(GJB6-D13S1830) mutation causes allele-specific loss of GJB2 expression in cis.	Rodriguez-Paris J	Biochemical and biophysical research communications	2009	PMID: 19723508
Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness.	Ahmad S	Proceedings of the National Academy of Sciences of the United States of America	2007	PMID: 17227867
Phenotypic variability of non-syndromic hearing loss in patients heterozygous for both c.35delG of GJB2 and the 342-kb deletion involving GJB6.	Bolz H	Hearing research	2004	PMID: 14759569
A deletion involving the connexin 30 gene in nonsyndromic hearing impairment.	del Castillo I	The New England journal of medicine	2002	PMID: 11807148

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NC_000013.10:g.(?_20797176)_(21105944_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...