NM_004004.6(GJB2):c.94C>A (p.Arg32Ser) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 15, 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:: RCV001861739.7

Allele description [Variation Report for NM_004004.6(GJB2):c.94C>A (p.Arg32Ser)]

NM_004004.6(GJB2):c.94C>A (p.Arg32Ser)

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.94C>A (p.Arg32Ser)

HGVS:

NC_000013.11:g.20189488G>T
NG_008358.1:g.8488C>A
NM_004004.6:c.94C>AMANE SELECT
NP_003995.2:p.Arg32Ser
LRG_1350t1:c.94C>A
LRG_1350:g.8488C>A
LRG_1350p1:p.Arg32Ser
NC_000013.10:g.20763627G>T
NM_004004.5:c.94C>A

Protein change:

R32S

Links:

dbSNP: rs371024165

NCBI 1000 Genomes Browser:

rs371024165

Molecular consequence:

NM_004004.6:c.94C>A - 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
SCV002243770	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 21112098, 24774219, 26553399, 31370293, 11102979, 19371219, 21465647, 26346709, 27045574, 28492532
SCV004034736	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 8, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002243770

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 15, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV004034736

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 8, 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

Prevalence of GJB2 causing recessive profound non-syndromic deafness in Japanese children.

Hayashi C, Funayama M, Li Y, Kamiya K, Kawano A, Suzuki M, Hattori N, Ikeda K.

Int J Pediatr Otorhinolaryngol. 2011 Feb;75(2):211-4. doi: 10.1016/j.ijporl.2010.11.001. Epub 2010 Nov 26.

PubMed [citation]

PMID:: 21112098

Particular distribution of the GJB2/GJB6 gene mutations in Mexican population with hearing impairment.

Loeza-Becerra F, Rivera-Vega Mdel R, Martínez-Saucedo M, Gonzalez-Huerta LM, Urueta-Cuellar H, Berrruecos-Villalobos P, Cuevas-Covarrubias S.

Int J Pediatr Otorhinolaryngol. 2014 Jul;78(7):1057-60. doi: 10.1016/j.ijporl.2014.04.002. Epub 2014 Apr 12.

PubMed [citation]

PMID:: 24774219

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002243770.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 32 of the GJB2 protein (p.Arg32Ser). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 21112098, 24774219, 26553399, 31370293). ClinVar contains an entry for this variant (Variation ID: 550195). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg32 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11102979, 19371219, 21465647, 26346709, 27045574). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

From GeneDx, SCV004034736.1

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

Description

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: 31370293, 21112098, 26553399, 24774219, 33753912)

#	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: Sep 29, 2024

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