NM_004004.6(GJB2):c.299A>T (p.His100Leu) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 2, 2018
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:: RCV000781416.1

Allele description [Variation Report for NM_004004.6(GJB2):c.299A>T (p.His100Leu)]

NM_004004.6(GJB2):c.299A>T (p.His100Leu)

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.299A>T (p.His100Leu)

HGVS:

NC_000013.11:g.20189283T>A
NG_008358.1:g.8693A>T
NM_004004.6:c.299A>TMANE SELECT
NP_003995.2:p.His100Leu
LRG_1350t1:c.299A>T
LRG_1350:g.8693A>T
LRG_1350p1:p.His100Leu
NC_000013.10:g.20763422T>A
NM_004004.5:c.299A>T

Protein change:

H100L

Links:

dbSNP: rs1422767764

NCBI 1000 Genomes Browser:

rs1422767764

Molecular consequence:

NM_004004.6:c.299A>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
SCV000919429	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Aug 2, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24256046, 26749107, 19371219 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000919429

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Aug 2, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Citations

PubMed

Prevalence of GJB2 mutations in the Silk Road region of China and a report of three novel variants.

Du W, Zhu YM, Guo YF, Wang QJ, Liu XW.

Acta Otolaryngol. 2014 Apr;134(4):373-81. doi: 10.3109/00016489.2013.849817. Epub 2013 Nov 21.

PubMed [citation]

PMID:: 24256046

The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis.

Kim HR, Oh SK, Lee ES, Choi SY, Roh SE, Kim SJ, Tsukihara T, Lee KY, Jeon CJ, Kim UK.

Hum Genet. 2016 Mar;135(3):287-98. doi: 10.1007/s00439-015-1625-7. Epub 2016 Jan 9.

PubMed [citation]

PMID:: 26749107

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919429.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: GJB2 c.299A>T (p.His100Leu) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) 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 3.2e-05 in 31172 control chromosomes (gnomAD and publication data). The variant, c.299A>T, has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (Primignani 2009, Du 2014). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Kim 2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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

Last Updated: May 1, 2024

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