NM_004004.6(GJB2):c.380G>T (p.Arg127Leu) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 8, 2019
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:: RCV000175760.7

Allele description [Variation Report for NM_004004.6(GJB2):c.380G>T (p.Arg127Leu)]

NM_004004.6(GJB2):c.380G>T (p.Arg127Leu)

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.380G>T (p.Arg127Leu)

HGVS:

NC_000013.11:g.20189202C>A
NG_008358.1:g.8774G>T
NM_004004.6:c.380G>TMANE SELECT
NP_003995.2:p.Arg127Leu
LRG_1350t1:c.380G>T
LRG_1350:g.8774G>T
LRG_1350p1:p.Arg127Leu
NC_000013.10:g.20763341C>A
NM_004004.5:c.380G>T

Protein change:

R127L

Links:

dbSNP: rs111033196

NCBI 1000 Genomes Browser:

rs111033196

Molecular consequence:

NM_004004.6:c.380G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000698254	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Apr 8, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17041943, 26346709, 26540915, 26749107, 29773520, 27466889 Citation Link,
SCV000710879	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jul 2, 2016)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17041943, 25388846, 26749107, 26540915, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000698254

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Apr 8, 2019)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV000710879

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jul 2, 2016)

germline

clinical testing

PubMed (5)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Mayan founder mutation is a common cause of deafness in Guatemala.

Carranza C, Menendez I, Herrera M, Castellanos P, Amado C, Maldonado F, Rosales L, Escobar N, Guerra M, Alvarez D, Foster J 2nd, Guo S, Blanton SH, Bademci G, Tekin M.

Clin Genet. 2016 Apr;89(4):461-465. doi: 10.1111/cge.12676. Epub 2015 Oct 6.

PubMed [citation]

PMID:: 26346709
PMCID:: PMC5484753

Frequency of GJB2 mutations in patients with nonsyndromic hearing loss from an ethnically characterized Brazilian population.

Felix F, Ribeiro MG, Tomita S, Zalis MG.

Braz J Otorhinolaryngol. 2019 Jan - Feb;85(1):92-98. doi: 10.1016/j.bjorl.2017.10.013. Epub 2017 Nov 21.

PubMed [citation]

PMID:: 29773520
PMCID:: PMC9442831

See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698254.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: GJB2 c.380G>T (p.Arg127Leu) results in a non-conservative amino acid change located in the Connexin, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 247720 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00027 vs 0.025), allowing no conclusion about variant significance. The variant, c.380G>T, has been reported in the literature without strong evidence for causality (Tang_2006, Cui_2015, Carranza_2015, , Gruber_2016, Felix_2019). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Non-Syndromic Hearing Loss. The variant displayed a defect in channel permeability in cell expressing homo-oligomeric GJ channels, but hetero-oligomeric GJ channels were no more than 50% or not significantly different from wt GJs, depending on the assay (Kim_2016). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000710879.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

The p.Arg127Leu variant in GJB2 has not been previously reported in individuals with hearing loss, but has been identified in 10/11538 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111 033196) and 3 control individuals (Tang 2008, Cui 2015). Although this variant h as been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Two other variants have been reported at the same amino acid position: the p.Arg127Cys variant of uncertain clinical significance and th e p.Arg127His which has been classified as benign. Computational prediction tool s and conservation analysis of the p.Arg127Leu variant do not provide strong sup port for or against an impact to the protein. In vitro studies suggest the varia nt may impact the protein (Yilmaz 2014, Kim 2016); however, these studies may no t accurately represent biological effects of the variant. In summary, the clinic al significance of the p.Arg127Leu variant is uncertain

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

Last Updated: Oct 8, 2024

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