NM_004004.6(GJB2):c.229T>C (p.Trp77Arg) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Aug 1, 2020
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:: RCV000018526.53

Allele description [Variation Report for NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)]

NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)

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.229T>C (p.Trp77Arg)

HGVS:

NC_000013.11:g.20189353A>G
NG_008358.1:g.8623T>C
NM_004004.6:c.229T>CMANE SELECT
NP_003995.2:p.Trp77Arg
NP_003995.2:p.Trp77Arg
LRG_1350t1:c.229T>C
LRG_1350:g.8623T>C
LRG_1350p1:p.Trp77Arg
NC_000013.10:g.20763492A>G
P29033:p.Trp77Arg
c.229T>C
c.229T>C (p.Trp77Arg)

Protein change:

W77R; TRP77ARG

Links:

UniProtKB: P29033#VAR_002141; OMIM: 121011.0004; dbSNP: rs104894397

NCBI 1000 Genomes Browser:

rs104894397

Molecular consequence:

NM_004004.6:c.229T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 1A (DFNB1A)
Synonyms:: Deafness nonsyndromic, Connexin 26 linked; Deafness, autosomal recessive 1A; DFNB 1 Nonsyndromic Hearing Loss and Deafness; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009076; MedGen: C2673759; Orphanet: 90636; OMIM: 220290

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038808	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000917453	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 21, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9328482, 16380907, 12505163, 16088916 Citation Link,
SCV001194211	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 9, 2019)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15967879, 22785241, 16380907, 10556284, 12505163 Citation Link,
SCV001244781	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 30, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001453346	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002059939	King Laboratory, University of Washington	criteria provided, single submitter (Abu Rayyan A et al. (Proc Natl Acad Sci U S A 2020))	Pathogenic (Aug 1, 2020)	germline	research	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations.

Carrasquillo MM, Zlotogora J, Barges S, Chakravarti A.

Hum Mol Genet. 1997 Nov;6(12):2163-72.

PubMed [citation]

PMID:: 9328482

High prevalence of the W24X mutation in the gene encoding connexin-26 (GJB2) in Spanish Romani (gypsies) with autosomal recessive non-syndromic hearing loss.

Alvarez A, del Castillo I, Villamar M, Aguirre LA, González-Neira A, López-Nevot A, Moreno-Pelayo MA, Moreno F.

Am J Med Genet A. 2005 Sep 1;137A(3):255-8.

PubMed [citation]

PMID:: 16088916

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000038808.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

One of 2 recessive mutations causing nonsyndromic recessive deafness (220290) observed in a Muslim Israeli-Arab village in the lower Galilee by Carrasquillo et al. (1997) was a T-to-C transition at cDNA position 229 that converted a tryptophan (TGG) into arginine (CGG).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917453.1

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

Description

Variant summary: GJB2 c.229T>C (p.Trp77Arg) results in a non-conservative amino acid change located in the connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 246400 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (4.1e-05 vs 0.025), allowing no conclusion about variant significance. c.229T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (Alvarez 2005, Carrasquillo 1997, Snoeckx 2005), and the variant was also found to segregate with the disease in one of these reported families (Carrasquillo 1997). These data indicate that the variant is very likely to be associated with disease. Functional studies have shown to have >99% reduction in junctional conductance in comparison to wild-type (Bruzzone_2003). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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

From Myriad Genetics, Inc., SCV001194211.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

NM_004004.5(GJB2):c.229T>C(W77R) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 15967879, 22785241, 16380907, 10556284 and 12505163. Classification of NM_004004.5(GJB2):c.229T>C(W77R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV001244781.1

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

Description

A homozygous missense variant was identified, NM_004004.5(GJB2):c.229T>C in exon 2 of the GJB2 gene. This substitution is predicted to create a major change from a tryptophan to an arginine at position 77, NP_003995.2(GJB2):p.(Trp77Arg). The tryptophan at this position has very high conservation (100 vertebrates, UCSC). In silico software predicts this variant to be disease causing. It is situated in the second transmembrane domain and functional studies have shown that it causes loss of channel activity. (Martin, PE. et al. (1999), Bruzzone, R. et al. (2002)). This variant is present in the gnomAD population database at a frequency of 0.0041% (10 in 246208, 0 homozygotes). It is one of the more frequent GJB2 variants and has been previously reported in patients with autosomal recessive deafness (Cryns, K. et al. (2004), Snoeckx, RL. et al. (2005), ClinVar). Based on current information, this variant has been classified as PATHOGENIC.

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

From Natera, Inc., SCV001453346.1

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

#	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 King Laboratory, University of Washington, SCV002059939.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

GJB2 c.229T>C, p.W77R alters a residue that is completely conserved in all sequenced vertebrates. The variant was previously reported to be deficient in formation of junctional channels (PMID: 18941476). The variant is homozygous in a Palestinian child with severe to profound pre-lingual hearing loss (Abu Rayyan 2020). It is not present in 1300 Palestinian controls and is present in 10/251404 alleles on gnomAD, all heterozygotes.

#	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

Last Updated: Nov 3, 2024

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