NM_004004.6(GJB2):c.224G>A (p.Arg75Gln) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 4, 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:: RCV000254728.17

Allele description [Variation Report for NM_004004.6(GJB2):c.224G>A (p.Arg75Gln)]

NM_004004.6(GJB2):c.224G>A (p.Arg75Gln)

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.224G>A (p.Arg75Gln)

HGVS:

NC_000013.11:g.20189358C>T
NG_008358.1:g.8618G>A
NM_004004.6:c.224G>AMANE SELECT
NP_003995.2:p.Arg75Gln
NP_003995.2:p.Arg75Gln
LRG_1350t1:c.224G>A
LRG_1350:g.8618G>A
LRG_1350p1:p.Arg75Gln
NC_000013.10:g.20763497C>T
NM_004004.5:c.224G>A
P29033:p.Arg75Gln

Protein change:

R75Q; ARG75GLN

Links:

UniProtKB: P29033#VAR_015936; OMIM: 121011.0026; dbSNP: rs28931593

NCBI 1000 Genomes Browser:

rs28931593

Molecular consequence:

NM_004004.6:c.224G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000322429	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 10, 2023)	germline	clinical testing	Citation Link,
SCV002247288	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12372058, 20815033, 24945352, 25153233, 27316387, 21040787, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000322429

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Feb 10, 2023)

germline

clinical testing

Citation Link,

SCV002247288

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2023)

germline

clinical testing

PubMed (7)
[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

The novel R75Q mutation in the GJB2 gene causes autosomal dominant hearing loss and palmoplantar keratoderma in a Turkish family.

Uyguner O, Tukel T, Baykal C, Eris H, Emiroglu M, Hafiz G, Ghanbari A, Baserer N, Yuksel-Apak M, Wollnik B.

Clin Genet. 2002 Oct;62(4):306-9.

PubMed [citation]

PMID:: 12372058

R75Q dominant mutation in GJB2 gene silenced by the in Cis recessive mutation c.35delG.

Iossa S, Chinetti V, Corvino V, Marciano E, Franzè A.

Am J Med Genet A. 2010 Oct;152A(10):2658-60. doi: 10.1002/ajmg.a.33630. No abstract available.

PubMed [citation]

PMID:: 20815033

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000322429.8

#	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 this variant prevents formation of functional channels (Piazza et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); 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: 21040787, 20096356, 20815033, 26088551, 20583176, 16059934, 33466560, 23451214, 25393658, 25153233, 29798269, 27316387, 25388846, 24975403, 24945352, 12372058, 29921236, 34599368, 15790391, 33096615, 15996214)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002247288.3

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 75 of the GJB2 protein (p.Arg75Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant GJB2-related conditions (PMID: 12372058, 20815033, 24945352, 25153233, 27316387). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17027). 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. Experimental studies have shown that this missense change affects GJB2 function (PMID: 21040787). 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 30, 2024

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