NM_004004.6(GJB2):c.563A>G (p.Lys188Arg) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 26, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000493772.7

Allele description [Variation Report for NM_004004.6(GJB2):c.563A>G (p.Lys188Arg)]

NM_004004.6(GJB2):c.563A>G (p.Lys188Arg)

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.563A>G (p.Lys188Arg)

HGVS:

NC_000013.11:g.20189019T>C
NG_008358.1:g.8957A>G
NM_004004.6:c.563A>GMANE SELECT
NP_003995.2:p.Lys188Arg
LRG_1350t1:c.563A>G
LRG_1350:g.8957A>G
LRG_1350p1:p.Lys188Arg
NC_000013.10:g.20763158T>C
NC_000013.10:g.20763158T>C
NM_004004.5:c.563A>G
NM_004004.6(GJB2):c.563A>GMANE SELECT
p.Lys188Arg

Protein change:

K188R

Links:

dbSNP: rs1131691709

NCBI 1000 Genomes Browser:

rs1131691709

Molecular consequence:

NM_004004.6:c.563A>G - 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
SCV000582691	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Apr 24, 2017)	germline	clinical testing	Citation Link,
SCV000698268	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Apr 21, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17666888, 25388846, 23967136 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV002179978	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 26, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17666888, 23967136, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000582691

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Apr 24, 2017)

germline

clinical testing

Citation Link,

SCV000698268

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Apr 21, 2016)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV002179978

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 26, 2023)

germline

clinical testing

PubMed (3)
[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

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

A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort.

Putcha GV, Bejjani BA, Bleoo S, Booker JK, Carey JC, Carson N, Das S, Dempsey MA, Gastier-Foster JM, Greinwald JH Jr, Hoffmann ML, Jeng LJ, Kenna MA, Khababa I, Lilley M, Mao R, Muralidharan K, Otani IM, Rehm HL, Schaefer F, Seltzer WK, Spector EB, et al.

Genet Med. 2007 Jul;9(7):413-26.

PubMed [citation]

PMID:: 17666888

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000582691.3

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

Description

The K188R variant in the GJB2 gene has been reported previously in association with autosomal recessive nonsyndromic sensorineural hearing loss (Putcha et al., 2007). The K188R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K188R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (R184G, R184W, R184Q, R184P, T186M, T186K, V190D) have been reported in the Human Gene Mutation Database in association with hearing loss (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret K188R as a pathogenic variant.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698268.1

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

Description

Variant summary: The c.563A>G variant involves the alteration of one of 5 invariant amino acid residues in the Connexin domain of GJB2 and 4/5 in silico tools predict a pathogenic outcome. The variant is absent from the large, broad ExAC control population and has been reported in the literature in two patients with hearing loss, at least one of whom also carried the known pathogenic GJB2 c.35delG variant in trans (Putcha_2007). Additionally, When expressed in HeLa cells, the K188R mutant failed to localize to cell membrane (Ambrosi_2013). Based on the highly conserved nature of the amino acid at position 563, despite limited clinical and functional data, this variant has been classified as a VUS - possibly pathogenic until additional evidence becomes available.

#	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, SCV002179978.3

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

Description

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 188 of the GJB2 protein (p.Lys188Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic sensorineural deafness (PMID: 17666888; external communication). 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: 429984). 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: 23967136). 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: Sep 29, 2024

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