NM_004004.6(GJB2):c.2T>C (p.Met1Thr) AND Nonsyndromic genetic hearing loss

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 28, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001171533.9

Allele description [Variation Report for NM_004004.6(GJB2):c.2T>C (p.Met1Thr)]

NM_004004.6(GJB2):c.2T>C (p.Met1Thr)

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.2T>C (p.Met1Thr)

HGVS:

NC_000013.11:g.20189580A>G
NG_008358.1:g.8396T>C
NM_004004.6:c.2T>CMANE SELECT
NP_003995.2:p.Met1Thr
LRG_1350t1:c.2T>C
LRG_1350:g.8396T>C
LRG_1350p1:p.Met1Thr
NC_000013.10:g.20763719A>G
NM_004004.5:c.2T>C
NM_004004.6(GJB2):c.2T>CMANE SELECT
p.Met1Thr

Protein change:

M1T

Links:

dbSNP: rs371086981

NCBI 1000 Genomes Browser:

rs371086981

Molecular consequence:

NM_004004.6:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_004004.6:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Nonsyndromic genetic hearing loss
Synonyms:: Nonsyndromic hearing loss and deafness; Non-syndromic genetic deafness; Nonsyndromic genetic deafness
Identifiers:: MONDO: MONDO:0019497; MedGen: C5680182; Orphanet: 87884

Recent activity

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Mus musculus A kinase (PRKA) anchor protein 2 (Akap2), mRNA
Mus musculus A kinase (PRKA) anchor protein 2 (Akap2), mRNA
gi|6753023|ref|NM_009649.1|

Nucleotide
cytochrome oxidase subunit 1, partial (mitochondrion) [Progne tapera]
cytochrome oxidase subunit 1, partial (mitochondrion) [Progne tapera]
gi|359284250|gb|AEV14353.1|

Protein
cytochrome c oxidase subunit II, partial (mitochondrion) [Progne tapera]
cytochrome c oxidase subunit II, partial (mitochondrion) [Progne tapera]
gi|19697680|gb|AAL13460.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000919428	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Aug 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001334318	ClinGen Hearing Loss Variant Curation Expert Panel	reviewed by expert panel (Clingen Hl Acmg Specifications Cdh23 Coch Gjb2 Kcnq4 Myo6 Myo7a Slc26a4 Tecta Ush2a V2)	Pathogenic (Mar 28, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000919428

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Aug 22, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001334318

ClinGen Hearing Loss Variant Curation Expert Panel

reviewed by expert panel

(Clingen Hl Acmg Specifications Cdh23 Coch Gjb2 Kcnq4 Myo6 Myo7a Slc26a4 Tecta Ush2a V2)

Pathogenic
(Mar 28, 2024)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Pathogenic Germline Variants in 10,389 Adult Cancers.

Huang KL, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, Paczkowska M, Reynolds S, Wyczalkowski MA, Oak N, Scott AD, Krassowski M, Cherniack AD, Houlahan KE, Jayasinghe R, Wang LB, Zhou DC, Liu D, Cao S, Kim YW, Koire A, McMichael JF, et al.

Cell. 2018 Apr 5;173(2):355-370.e14. doi: 10.1016/j.cell.2018.03.039.

PubMed [citation]

PMID:: 29625052
PMCID:: PMC5949147

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919428.3

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

Description

Variant summary: GJB2 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249204 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2T>C in individuals affected with Non-Syndromic Hearing Loss and no experimental evidence demonstrating its impact on protein function have been reported. This variant disrupts the start codon for protein translation (ATG becomes ACG) and the next start codon is 32 amino acids downstream. Variants affecting the same codon (M1V) and other codons within the N terminal 32 amino acids (such as L6P, Q7P, L10P, G12V, R32C, etc) have been reported in many affected individuals, suggesting the functional importance of this codon and the N terminal region of this protein (example: PMID: 29605365, PMID: 9482292). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic(n=3)/likely pathogenic(n=2). Based on the evidence outlined above, the variant was classified as likely 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 ClinGen Hearing Loss Variant Curation Expert Panel, SCV001334318.3

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

Description

The c.2T>C (p.Met1Thr) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 2070085, 550716, 551915). This variant has been observed in 0.0074% (8/107882) of the African population in the All of Us database (PM2_Supporting). It was identified in 1 patient with bilateral sensorineural hearing loss who also harbored an assumed trans pathogenic variant (0.5 PM3_Supporting points; Athena Diagnostics internal data, SCV001143666.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3_Supporting (VCEP specifications version 2; 10.18.2023).

#	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: Oct 26, 2024

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