NM_004004.6(GJB2):c.279G>A (p.Met93Ile) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 25, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000523752.21

Allele description [Variation Report for NM_004004.6(GJB2):c.279G>A (p.Met93Ile)]

NM_004004.6(GJB2):c.279G>A (p.Met93Ile)

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.279G>A (p.Met93Ile)

HGVS:

NC_000013.11:g.20189303C>T
NG_008358.1:g.8673G>A
NM_004004.6:c.279G>AMANE SELECT
NP_003995.2:p.Met93Ile
LRG_1350t1:c.279G>A
LRG_1350:g.8673G>A
LRG_1350p1:p.Met93Ile
NC_000013.10:g.20763442C>T
NM_004004.5:c.279G>A
P29033:p.Met93Ile
c.279G>A

Protein change:

M93I

Links:

UniProtKB: P29033#VAR_023609; dbSNP: rs397516871

NCBI 1000 Genomes Browser:

rs397516871

Molecular consequence:

NM_004004.6:c.279G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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RecName: Full=Transmembrane protein 209
RecName: Full=Transmembrane protein 209
gi|187663981|sp|Q96SK2.2|TM209_HUMA

Protein
Sarcophilus harrisii isolate Salem Chr3_contig_000030696, whole genome shotgun s...
Sarcophilus harrisii isolate Salem Chr3_contig_000030696, whole genome shotgun sequence
gi|322953326|gb|AEFK01134165.1||gnl AEFK01|Chr3_contig_000030696

Nucleotide
unnamed protein product [Mus musculus]
unnamed protein product [Mus musculus]
gi|26326543|dbj|BAC27015.1|

Protein
Homo sapiens cDNA FLJ16247 fis, clone HCHON2003659, highly similar to LAMIN A
Homo sapiens cDNA FLJ16247 fis, clone HCHON2003659, highly similar to LAMIN A
gi|34527925|dbj|AK122732.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000617688	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Jan 21, 2024)	germline	clinical testing	Citation Link,
SCV002048130	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Likely pathogenic (Oct 21, 2021)	germline	clinical testing	Citation Link,
SCV002274257	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12172394, 14985372, 22592158, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000617688

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Jan 21, 2024)

germline

clinical testing

Citation Link,

SCV002048130

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Likely pathogenic
(Oct 21, 2021)

germline

clinical testing

Citation Link,

SCV002274257

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 25, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing.

Wu BL, Lindeman N, Lip V, Adams A, Amato RS, Cox G, Irons M, Kenna M, Korf B, Raisen J, Platt O.

Genet Med. 2002 Jul-Aug;4(4):279-88.

PubMed [citation]

PMID:: 12172394

A genotype-phenotype correlation for GJB2 (connexin 26) deafness.

Cryns K, Orzan E, Murgia A, Huygen PL, Moreno F, del Castillo I, Chamberlin GP, Azaiez H, Prasad S, Cucci RA, Leonardi E, Snoeckx RL, Govaerts PJ, Van de Heyning PH, Van de Heyning CM, Smith RJ, Van Camp G.

J Med Genet. 2004 Mar;41(3):147-54.

PubMed [citation]

PMID:: 14985372
PMCID:: PMC1735685

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000617688.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18776652, 16380907, 14985372, 25616557, 17666888, 20497192, 20668687, 12172394, 25388846, 22592158, 22695344, 30708180, 24156272, 15666300, 36478599, 30245029, 28483220, 25555641, 25447126)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048130.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The GJB2 c.279G>A; p.Met93Ile variant (rs397516871) is reported in the literature in multiple individuals affected with hearing loss often found with a second pathogenic variant (Cryns 2004, Naghavi 2008, Najmabadi 2005, Putcha 2007, Wu 2002). This variant is also reported in ClinVar (Variation ID: 44733). This variant is found in the non-Finnish European population with an allele frequency of 0.003% (3/113608 alleles) in the Genome Aggregation Database. The methionine at codon 93 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.874). Based on available information, this variant is considered to be likely pathogenic. References: Cryns K et al. A genotype-phenotype correlation for GJB2 (connexin 26) deafness. J Med Genet. 2004 Mar;41(3):147-54. PMID: 14985372. Naghavi A et al. GJB2 mutations in Baluchi population. J Genet. 2008 Aug;87(2):195-7. PMID: 18776652. Najmabadi H et al. GJB2 mutations: passage through Iran. Am J Med Genet A. 2005 Mar 1;133A(2):132-7. PMID: 15666300. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. PMID: 17666888. Wu BL et al. Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. Genet Med. 2002 Jul-Aug;4(4):279-88. PMID: 12172394.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002274257.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 93 of the GJB2 protein (p.Met93Ile). This variant is present in population databases (rs397516871, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 12172394, 14985372). ClinVar contains an entry for this variant (Variation ID: 44733). 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) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 22592158). This variant disrupts the p.Met93 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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