NM_004004.6(GJB2):c.250G>T (p.Val84Leu) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 3, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000169112.16

Allele description [Variation Report for NM_004004.6(GJB2):c.250G>T (p.Val84Leu)]

NM_004004.6(GJB2):c.250G>T (p.Val84Leu)

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.250G>T (p.Val84Leu)

HGVS:

NC_000013.11:g.20189332C>A
NG_008358.1:g.8644G>T
NM_004004.6:c.250G>TMANE SELECT
NP_003995.2:p.Val84Leu
NP_003995.2:p.Val84Leu
LRG_1350t1:c.250G>T
LRG_1350:g.8644G>T
LRG_1350p1:p.Val84Leu
NC_000013.10:g.20763471C>A
NM_004004.5:c.250G>T
P29033:p.Val84Leu

Protein change:

V84L

Links:

UniProtKB: P29033#VAR_002143; dbSNP: rs104894409

NCBI 1000 Genomes Browser:

rs104894409

Molecular consequence:

NM_004004.6:c.250G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 1A (DFNB1A)
Synonyms:: Deafness nonsyndromic, Connexin 26 linked; Deafness, autosomal recessive 1A; DFNB 1 Nonsyndromic Hearing Loss and Deafness; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009076; MedGen: C2673759; Orphanet: 90636; OMIM: 220290

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220314	Counsyl	no assertion criteria provided	Pathogenic (Nov 13, 2017)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 12505163, 16849369, 26346709, 17666888, 11556849, 24013081, 16217030, 12562518, 26778469, 20441744, 23555729, 14985372, 11313763, 15592461
SCV001437384	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 3, 2020)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11556849, 16380907, 12505163, 12562518, 12172394, 17666888, 15592461, 16217030, 20441744, 26346709, 24013081 Citation Link,
SCV002086056	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 3, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000220314

Counsyl

no assertion criteria provided

Pathogenic
(Nov 13, 2017)

unknown

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV001437384

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 3, 2020)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link,

SCV002086056

Natera, Inc.

no assertion criteria provided

Pathogenic
(Aug 3, 2020)

germline

clinical testing

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Pathogenetic role of the deafness-related M34T mutation of Cx26.

Bicego M, Beltramello M, Melchionda S, Carella M, Piazza V, Zelante L, Bukauskas FF, Arslan E, Cama E, Pantano S, Bruzzone R, D'Andrea P, Mammano F.

Hum Mol Genet. 2006 Sep 1;15(17):2569-87. Epub 2006 Jul 18.

PubMed [citation]

PMID:: 16849369
PMCID:: PMC2829448

Prevalence and audiological profiles of GJB2 mutations in a large collective of hearing impaired patients.

Burke WF, Warnecke A, Schöner-Heinisch A, Lesinski-Schiedat A, Maier H, Lenarz T.

Hear Res. 2016 Mar;333:77-86. doi: 10.1016/j.heares.2016.01.006. Epub 2016 Jan 15.

PubMed [citation]

PMID:: 26778469

See all PubMed Citations (16)

Details of each submission

From Counsyl, SCV000220314.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	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, SCV001437384.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

Variant summary: GJB2 c.250G>T (p.Val84Leu) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251338 control chromosomes (gnomAD). c.250G>T has been reported in the literature, in the compound heterozygous and homozygous state, in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Kenna_2001, Wu_2002, Snoeckx_2005, Putcha_2007, Minami_2013, Carranza_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant retains electrophysiological properties but affects the intercellular exchange of large molecules (such as IP3 transfer) (e.g. Bruzzone_2003, Wang_2003, Beltramello_2005, Zhang_2005, Ambrosi_2010). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Natera, Inc., SCV002086056.1

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

#	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 3, 2024

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