NM_004004.6(GJB2):c.56G>C (p.Ser19Thr) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 26, 2023
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:: RCV000757333.15

Allele description [Variation Report for NM_004004.6(GJB2):c.56G>C (p.Ser19Thr)]

NM_004004.6(GJB2):c.56G>C (p.Ser19Thr)

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.56G>C (p.Ser19Thr)

Other names:

NM_004004.5(GJB2):c.56G>C; NM_004004.6(GJB2):c.56G>C

HGVS:

NC_000013.11:g.20189526C>G
NG_008358.1:g.8450G>C
NM_004004.6:c.56G>CMANE SELECT
NP_003995.2:p.Ser19Thr
LRG_1350t1:c.56G>C
LRG_1350:g.8450G>C
LRG_1350p1:p.Ser19Thr
NC_000013.10:g.20763665C>G
NM_004004.5:c.56G>C

Protein change:

S19T

Links:

dbSNP: rs80338941

NCBI 1000 Genomes Browser:

rs80338941

Molecular consequence:

NM_004004.6:c.56G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000885517	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Jan 8, 2018)	germline	clinical testing	Citation Link,
SCV001415840	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 26, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 26188157, 12176036, 10982180, 15146474, 16077952, 24158611, 28492532
SCV004014337	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 13, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000885517

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Likely pathogenic
(Jan 8, 2018)

germline

clinical testing

Citation Link,

SCV001415840

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 26, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004014337

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 13, 2023)

germline

clinical testing

Citation Link

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

Spectrum and frequency of GJB2, GJB6 and SLC26A4 gene mutations among nonsyndromic hearing loss patients in eastern part of India.

Adhikary B, Ghosh S, Paul S, Bankura B, Pattanayak AK, Biswas S, Maity B, Das M.

Gene. 2015 Dec 1;573(2):239-45. doi: 10.1016/j.gene.2015.07.050. Epub 2015 Jul 16.

PubMed [citation]

PMID:: 26188157

Hearing loss: frequency and functional studies of the most common connexin26 alleles.

D'Andrea P, Veronesi V, Bicego M, Melchionda S, Zelante L, Di Iorio E, Bruzzone R, Gasparini P.

Biochem Biophys Res Commun. 2002 Aug 23;296(3):685-91.

PubMed [citation]

PMID:: 12176036

See all PubMed Citations (7)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885517.1

#	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.56G>C; p.Ser19Thr variant (rs80338941) has been reported in individuals with hearing loss and has been found in trans with the pathogenic 35delG variant (D'Andrea 2002, Putcha 2007, Rabionet 2000). Functional studies show the variant protein has normal expression but is unable to form functional gap-junction channels in HeLa cells (D'Andrea 2002). This variant is reported in ClinVar (Variation ID: 21389) and observed in the general population with an overall allele frequency of 0.001% (3/244518 alleles) in the Genome Aggregation Database. Based on the above information, this variant is considered likely pathogenic. REFERENCES D'Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 Aug 23;296(3):685-91. 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. Rabionet R et al. Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet. 2000 Jan;106(1):40-4.

#	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, SCV001415840.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser19 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (PMID: 26188157), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GJB2 function (PMID: 12176036). 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. ClinVar contains an entry for this variant (Variation ID: 21389). This missense change has been observed in individuals with non-syndromic deafness (PMID: 10982180, 15146474, 16077952, 24158611). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs80338941, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 19 of the GJB2 protein (p.Ser19Thr).

#	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 GeneDx, SCV004014337.1

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

Description

Published functional studies demonstrate the p.S19T variant results in near total loss of function for gap-junction channels (D'Andrea et al., 2002); Observed multiple times with a pathogenic variant in unrelated patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Shen et al., 2019; Buonfiglio et al., 2020; Dalamon et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16077952, 26553399, 12176036, 33096615, 16380907, 35457072, 19230829, 11439000, 10982180, 19285578, 15070423, 25388846, 15146474, 24158611, 31160754, 16950989)

#	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: Oct 26, 2024

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