NM_004004.6(GJB2):c.128T>C (p.Val43Ala) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 12, 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:: RCV003127019.6

Allele description [Variation Report for NM_004004.6(GJB2):c.128T>C (p.Val43Ala)]

NM_004004.6(GJB2):c.128T>C (p.Val43Ala)

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.128T>C (p.Val43Ala)

HGVS:

NC_000013.11:g.20189454A>G
NG_008358.1:g.8522T>C
NM_004004.6:c.128T>CMANE SELECT
NP_003995.2:p.Val43Ala
LRG_1350t1:c.128T>C
LRG_1350:g.8522T>C
LRG_1350p1:p.Val43Ala
NC_000013.10:g.20763593A>G
NM_004004.5:c.128T>C

Protein change:

V43A

Molecular consequence:

NM_004004.6:c.128T>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
SCV003803248	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Sep 6, 2023)	germline	clinical testing	Citation Link,
SCV004680611	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 12, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12792423, 26043044, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003803248

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Sep 6, 2023)

germline

clinical testing

Citation Link,

SCV004680611

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 12, 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

Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness.

Hwa HL, Ko TM, Hsu CJ, Huang CH, Chiang YL, Oong JL, Chen CC, Hsu CK.

Genet Med. 2003 May-Jun;5(3):161-5.

PubMed [citation]

PMID:: 12792423

GJB2 Mutation Spectrum and Genotype-Phenotype Correlation in 1067 Han Chinese Subjects with Non-Syndromic Hearing Loss.

Zheng J, Ying Z, Cai Z, Sun D, He Z, Gao Y, Zhang T, Zhu Y, Chen Y, Guan MX.

PLoS One. 2015;10(6):e0128691. doi: 10.1371/journal.pone.0128691.

PubMed [citation]

PMID:: 26043044
PMCID:: PMC4456361

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV003803248.3

#	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26043044)

#	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, SCV004680611.1

#	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 valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 43 of the GJB2 protein (p.Val43Ala). This variant is present in population databases (rs776267945, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GJB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2429565). 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. This variant disrupts the p.Val43 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (PMID: 12792423, 26043044), which suggests that this may be a clinically significant amino acid residue. 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

Last Updated: Sep 29, 2024

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