VCV000311382.16 - ClinVar

NM_001110219.3(GJB6):c.63del (p.Lys22fs)

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.

(5)

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
Likely pathogenic(2); Uncertain significance(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001110219.3(GJB6):c.63del (p.Lys22fs)

Variation ID: 311382 Accession: VCV000311382.16

Type and length

Deletion, 1 bp

Location

Cytogenetic: 13q12.11 13: 20223418 (GRCh38) [ NCBI UCSC ] 13: 20797557 (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	Dec 6, 2016	Mar 4, 2023	Jun 7, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001110219.3:c.63del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001103689.1:p.Lys22fs	frameshift
NM_001110220.3:c.63del	NP_001103690.1:p.Lys22fs	frameshift
NM_001110221.3:c.63del	NP_001103691.1:p.Lys22fs	frameshift
NM_001370090.1:c.63del	NP_001357019.1:p.Lys22fs	frameshift
NM_001370091.1:c.63del	NP_001357020.1:p.Lys22fs	frameshift
NM_001370092.1:c.63del	NP_001357021.1:p.Lys22fs	frameshift
NM_006783.4:c.63delG
NM_006783.5:c.63del	NP_006774.2:p.Lys22fs	frameshift
NC_000013.11:g.20223420del
NC_000013.10:g.20797559del
NG_008323.1:g.13978del
LRG_1395:g.13978del
LRG_1395t1:c.63del	LRG_1395p1:p.Lys22fs

... more HGVS ... less HGVS

Protein change

K22fs

Other names

Canonical SPDI

NC_000013.11:20223417:CCC:CC

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

ClinGen: CA6904516 dbSNP: rs770612890 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.
GJB6		No evidence available	No evidence available	GRCh38 GRCh37	195	279

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	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 7, 2021	RCV000440483.6
Hidrotic ectodermal dysplasia syndrome	Likely pathogenic (1)	criteria provided, single submitter	Jul 22, 2016	RCV000409500.2
Autosomal dominant nonsyndromic hearing loss 3B Autosomal recessive nonsyndromic hearing loss 1A Autosomal recessive nonsyndromic hearing loss 1B Hidrotic ectodermal dysplasia syndrome	Uncertain significance (1)	criteria provided, single submitter	Jun 7, 2022	RCV001221511.6
GJB6-related disorder	Uncertain significance (1)	criteria provided, single submitter	May 3, 2018	RCV004529553.1

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.
Likely pathogenic (Feb 10, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511699.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Uncertain significance (May 03, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	GJB6-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000383104.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (1) PubMed: 25262649 Comment: The GJB6 c.63delG (p.Lys22ArgfsTer13) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed … (more) The GJB6 c.63delG (p.Lys22ArgfsTer13) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.00070 in the African American population of the Exome Sequencing Project. Based on the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for GJB6-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Likely pathogenic (Jul 22, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Hidrotic ectodermal dysplasia syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000487352.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 25262649‚ 16950989
Uncertain significance (Jun 07, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal dominant nonsyndromic hearing loss 3B Hidrotic ectodermal dysplasia syndrome Autosomal recessive nonsyndromic hearing loss 1B Autosomal recessive nonsyndromic hearing loss 1A Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001393560.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 16547895 Comment: This sequence change creates a premature translational stop signal (p.Lys22Argfs13) in the GJB6 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Lys22Argfs13) in the GJB6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 240 amino acid(s) of the GJB6 protein. This variant is present in population databases (rs770612890, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with profound, congenital non-syndromic hearing loss (PMID: 16547895). ClinVar contains an entry for this variant (Variation ID: 311382). 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)
Uncertain significance (May 07, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002012772.2 First in ClinVar: Nov 12, 2021 Last updated: Mar 04, 2023	Comment: Frameshift variant predicted to result in protein truncation as the last 240 amino acids are replaced with 12 different amino acids, although loss-of-function variants have … (more) Frameshift variant predicted to result in protein truncation as the last 240 amino acids are replaced with 12 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 25262649, 16950989, 30245029) (less)

Comment:

The GJB6 c.63delG (p.Lys22ArgfsTer13) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.00070 in the African American population of the Exome Sequencing Project. Based on the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for GJB6-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

This sequence change creates a premature translational stop signal (p.Lys22Argfs*13) in the GJB6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 240 amino acid(s) of the GJB6 protein. This variant is present in population databases (rs770612890, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with profound, congenital non-syndromic hearing loss (PMID: 16547895). ClinVar contains an entry for this variant (Variation ID: 311382). 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.

Comment:

Frameshift variant predicted to result in protein truncation as the last 240 amino acids are replaced with 12 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 25262649, 16950989, 30245029)

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
Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants.	Shearer AE	American journal of human genetics	2014	PMID: 25262649
Simultaneous multigene mutation detection in patients with sensorineural hearing loss through a novel diagnostic microarray: a new approach for newborn screening follow-up.	Gardner P	Pediatrics	2006	PMID: 16950989
[Pseudodominants of two recessive connexin mutations in non-syndromic sensorineural hearing loss?].	Birkenhäger R	Laryngo- rhino- otologie	2006	PMID: 16547895

Text-mined citations for rs770612890 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001110219.3(GJB6):c.63del (p.Lys22fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs770612890 ...