VCV000438615.9 - ClinVar

NM_004004.6(GJB2):c.60T>G (p.Ile20Met)

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.

(7)

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(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004004.6(GJB2):c.60T>G (p.Ile20Met)

Variation ID: 438615 Accession: VCV000438615.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q12.11 13: 20189522 (GRCh38) [ NCBI UCSC ] 13: 20763661 (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	Sep 19, 2017	Jul 15, 2024	May 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004004.6:c.60T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003995.2:p.Ile20Met	missense
NC_000013.11:g.20189522A>C
NC_000013.10:g.20763661A>C
NG_008358.1:g.8454T>G
LRG_1350:g.8454T>G
LRG_1350t1:c.60T>G	LRG_1350p1:p.Ile20Met

... more HGVS ... less HGVS

Protein change

I20M

Other names

Canonical SPDI

NC_000013.11:20189521:A:C

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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

ClinGen: CA6904326 dbSNP: rs749693224 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

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.
Autosomal recessive nonsyndromic hearing loss 1A	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2018	RCV000505534.5
Autosomal dominant nonsyndromic hearing loss 3A	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 8, 2024	RCV001112642.5
Ichthyosis, hystrix-like, with hearing loss	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001112643.4
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jan 15, 2024	RCV001857232.4

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.
Uncertain significance (May 09, 2017)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Deafness, autosomal recessive 1A Affected status: yes Allele origin: germline	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000599726.1 First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017	Number of individuals with the variant: 1
Uncertain significance (Jan 31, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Autosomal recessive nonsyndromic hearing loss 1A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000797602.1 First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017	Publications: PubMed (3) PubMed: 17666888‚ 12910486‚ 12172394
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal dominant nonsyndromic hearing loss 3A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001270325.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 12172394‚ 12910486 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ichthyosis, hystrix-like, with hearing loss Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001270326.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal recessive nonsyndromic hearing loss 1A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001270327.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely pathogenic (Jan 15, 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: SCV002261512.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 12172394‚ 12910486‚ 17666888‚ 11313763‚ 12189487‚ 16217030‚ 16380907 Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 20 of the GJB2 protein (p.Ile20Met). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 20 of the GJB2 protein (p.Ile20Met). This variant is present in population databases (rs749693224, gnomAD 0.08%). This missense change has been observed in individual(s) with deafness (PMID: 12172394, 12910486, 17666888; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 438615). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. This variant disrupts the p.Ile20 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11313763, 12189487, 16217030, 16380907). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Likely pathogenic (May 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Autosomal dominant nonsyndromic hearing loss 3A Affected status: yes Allele origin: germline	Laboratory of Prof. Karen Avraham, Tel Aviv University Accession: SCV005073751.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 Comment: DFNA3A; high-tone HL, normal-moderate	Comment: Pathogenic by Deafness Variation Database and suggested as autosomal dominant according to PMID: 12172394 Number of individuals with the variant: 1 Ethnicity/Population group: Jewish Geographic origin: Israel Testing laboratory: Prof. Karen Avraham, Tel Aviv University, Israel Date variant was reported to submitter: 2024-05-08

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 20 of the GJB2 protein (p.Ile20Met). This variant is present in population databases (rs749693224, gnomAD 0.08%). This missense change has been observed in individual(s) with deafness (PMID: 12172394, 12910486, 17666888; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 438615). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. This variant disrupts the p.Ile20 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11313763, 12189487, 16217030, 16380907). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort.	Putcha GV	Genetics in medicine : official journal of the American College of Medical Genetics	2007	PMID: 17666888
GJB2 mutations and degree of hearing loss: a multicenter study.	Snoeckx RL	American journal of human genetics	2005	PMID: 16380907
Gap junction-mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions.	Zhang Y	Proceedings of the National Academy of Sciences of the United States of America	2005	PMID: 16217030
Use of a multiplex PCR/sequencing strategy to detect both connexin 30 (GJB6) 342 kb deletion and connexin 26 (GJB2) mutations in cases of childhood deafness.	Wu BL	American journal of medical genetics. Part A	2003	PMID: 12910486
Progressive hearing loss, and recurrent sudden sensorineural hearing loss associated with GJB2 mutations--phenotypic spectrum and frequencies of GJB2 mutations in Austria.	Janecke AR	Human genetics	2002	PMID: 12189487
Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing.	Wu BL	Genetics in medicine : official journal of the American College of Medical Genetics	2002	PMID: 12172394
Sensorineural hearing loss and the incidence of Cx26 mutations in Austria.	Löffler J	European journal of human genetics : EJHG	2001	PMID: 11313763

Text-mined citations for rs749693224 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004004.6(GJB2):c.60T>G (p.Ile20Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs749693224 ...