NM_004004.6(GJB2):c.380G>T (p.Arg127Leu) AND not provided

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Jan 20, 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:: RCV000587104.20

Allele description [Variation Report for NM_004004.6(GJB2):c.380G>T (p.Arg127Leu)]

NM_004004.6(GJB2):c.380G>T (p.Arg127Leu)

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.380G>T (p.Arg127Leu)

HGVS:

NC_000013.11:g.20189202C>A
NG_008358.1:g.8774G>T
NM_004004.6:c.380G>TMANE SELECT
NP_003995.2:p.Arg127Leu
LRG_1350t1:c.380G>T
LRG_1350:g.8774G>T
LRG_1350p1:p.Arg127Leu
NC_000013.10:g.20763341C>A
NM_004004.5:c.380G>T

Protein change:

R127L

Links:

dbSNP: rs111033196

NCBI 1000 Genomes Browser:

rs111033196

Molecular consequence:

NM_004004.6:c.380G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000227300	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Dec 13, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000841708	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (Mar 12, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17041943, 26749107, 25388846, 26467025
SCV003298406	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 20, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26346709, 29773520, 26749107, 28492532
SCV003816810	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 16, 2020)	germline	clinical testing	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls.

Tang HY, Fang P, Ward PA, Schmitt E, Darilek S, Manolidis S, Oghalai JS, Roa BB, Alford RL.

Am J Med Genet A. 2006 Nov 15;140(22):2401-15. Erratum in: Am J Med Genet A. 2008 Nov 15;146A(22):2979..

PubMed [citation]

PMID:: 17041943
PMCID:: PMC3623690

Bioinformatic Analysis of GJB2 Gene Missense Mutations.

Yilmaz A.

Cell Biochem Biophys. 2015 Apr;71(3):1623-42. doi: 10.1007/s12013-014-0385-7.

PubMed [citation]

PMID:: 25388846

See all PubMed Citations (8)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000227300.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

#	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		3	not provided	not provided	not provided

From Athena Diagnostics, SCV000841708.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (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 GeneDx, SCV002015572.5

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

Description

Identified in a cohort of nonsyndromic hearing loss patients in Guatemala and Brazil in published literature (Carranza et al., 2015; Felix et al., 2019); Published functional studies suggest a damaging effect (Kim et al., 2016); 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: 30245029, 25388846, 17041943, 26540915, 27466889, 32596493, 29773520, 34652575, 34599368, 26346709, 26749107, 37106706)

#	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 Invitae, SCV003298406.2

#	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 arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 127 of the GJB2 protein (p.Arg127Leu). This variant is present in population databases (rs111033196, gnomAD 0.2%). This missense change has been observed in individual(s) with bilateral hearing loss and/or deafness (PMID: 26346709, 29773520; 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: 195204). 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. Experimental studies have shown that this missense change affects GJB2 function (PMID: 26749107). 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.

#	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 Revvity Omics, Revvity, SCV003816810.2

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

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002015572	GeneDx	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Jul 7, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002015572

GeneDx

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Jul 7, 2023)

germline

clinical testing

Citation Link

Last Updated: May 7, 2024

ClinVar

Relating variation to medicine