NM_004004.6(GJB2):c.250G>C (p.Val84Leu) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 14, 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:: RCV001041795.11

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

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

HGVS:

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

Protein change:

V84L; VAL84LEU

Links:

UniProtKB: P29033#VAR_002143; OMIM: 121011.0032; dbSNP: rs104894409

NCBI 1000 Genomes Browser:

rs104894409

Molecular consequence:

NM_004004.6:c.250G>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
SCV001205435	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 14, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 11556849, 12172394, 16380907, 19235794, 24013081, 26346709, 12505163, 12562518, 15592461, 16217030, 20441744, 28492532
SCV001476374	Athena Diagnostics Inc	criteria provided, single submitter (Athena Diagnostics criteria)	Pathogenic (May 26, 2021)	unknown	clinical testing	PubMed (24) [See all records that cite these PMIDs] 26188157, 24158611, 23555729, 22925408, 17426645, 17041943, 16849369, 16380907, 16217030, 14985372, 12562518, 12497637, 11556849, 10049954, 25388846, 12189487, 12505163, 15365987, 15592461, 17666888, 20083784, 20441744, 9529365, 26467025
SCV001770240	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 15, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001205435

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 14, 2023)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV001476374

Athena Diagnostics Inc

criteria provided, single submitter

(Athena Diagnostics criteria)

Pathogenic
(May 26, 2021)

unknown

clinical testing

PubMed (24)
[See all records that cite these PMIDs]

SCV001770240

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 15, 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	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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing.

Wu BL, Lindeman N, Lip V, Adams A, Amato RS, Cox G, Irons M, Kenna M, Korf B, Raisen J, Platt O.

Genet Med. 2002 Jul-Aug;4(4):279-88.

PubMed [citation]

PMID:: 12172394

Audiologic and temporal bone imaging findings in patients with sensorineural hearing loss and GJB2 mutations.

Lee KH, Larson DA, Shott G, Rasmussen B, Cohen AP, Benton C, Halsted M, Choo D, Meinzen-Derr J, Greinwald JH Jr.

Laryngoscope. 2009 Mar;119(3):554-8. doi: 10.1002/lary.20162.

PubMed [citation]

PMID:: 19235794
PMCID:: PMC7065710

See all PubMed Citations (29)

Details of each submission

From Invitae, SCV001205435.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Leu). This variant is present in population databases (rs104894409, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 11556849, 12172394, 16380907, 19235794, 24013081, 26346709). ClinVar contains an entry for this variant (Variation ID: 17032). 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%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 12505163, 12562518, 15592461, 16217030, 20441744). 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 Athena Diagnostics Inc, SCV001476374.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (24)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant results in impaired permeability to larger molecules, such as inositol 1,4,5-trisphosphate (PMID: 15592461, 16217030). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.

#	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 GeneDx, SCV001770240.2

#	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 a damaging effect on biochemical permeability, while ionic coupling is intact (Zhang et al., 2005); 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: 17426645, 24158611, 23555729, 15365987, 25087612, 25388846, 15592461, 16380907, 14985372, 12562518, 12505163, 20441744, 16217030, 9529365, 17666888, 12189487, 11556849, 31160754, 33096615, 31589614, 34308104, 31331740)

#	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: Feb 20, 2024

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