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NM_004004.6(GJB2):c.269T>C (p.Leu90Pro) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 10, 2021
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:
RCV003224102.8

Allele description [Variation Report for NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)]

NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)

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.269T>C (p.Leu90Pro)
HGVS:
  • NC_000013.11:g.20189313A>G
  • NG_008358.1:g.8663T>C
  • NM_004004.6:c.269T>CMANE SELECT
  • NP_003995.2:p.Leu90Pro
  • NP_003995.2:p.Leu90Pro
  • LRG_1350t1:c.269T>C
  • LRG_1350:g.8663T>C
  • LRG_1350p1:p.Leu90Pro
  • NC_000013.10:g.20763452A>G
  • NM_004004.5:c.269T>C
  • P29033:p.Leu90Pro
  • c.269T>C
  • c.269T>C (p.Leu90Pro)
  • p.LEU90PRO
Protein change:
L90P; LEU90PRO
Links:
UniProtKB: P29033#VAR_015937; OMIM: 121011.0016; dbSNP: rs80338945
NCBI 1000 Genomes Browser:
rs80338945
Molecular consequence:
  • NM_004004.6:c.269T>C - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
loss_of_function_variant [Sequence Ontology: SO:0002054]

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
Name:
Mutilating keratoderma (VOWNKL)
Synonyms:
Deafness, congenital, with keratopachydermia and constrictions of fingers and toes; Keratoderma hereditarium mutilans
Identifiers:
MONDO: MONDO:0007422; MedGen: C0265964; Orphanet: 494; OMIM: 124500
Name:
Ichthyosis, hystrix-like, with hearing loss
Synonyms:
HID SYNDROME; Hystrix-like ichthyosis with deafness
Identifiers:
MONDO: MONDO:0011245; MedGen: C1865234; Orphanet: 477; OMIM: 602540
Name:
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome
Synonyms:
Keratitis-ichthyosis-deafness syndrome, autosomal dominant; KID syndrome, autosomal dominant; Senter syndrome
Identifiers:
MONDO: MONDO:0007850; MedGen: C0265336; Orphanet: 477; OMIM: 148210
Name:
Palmoplantar keratoderma-deafness syndrome
Synonyms:
Keratoderma palmoplantar deafness; Keratoderma palmoplantar, with deafness; Palmoplantar keratoderma and sensorineural deafness; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007852; MedGen: C1835672; Orphanet: 2202; OMIM: 148350
Name:
Knuckle pads, deafness AND leukonychia syndrome
Synonyms:
Knuckle pads, leuconychia and sensorineural deafness; Bart-Pumphrey syndrome
Identifiers:
MONDO: MONDO:0007866; MedGen: C0266004; Orphanet: 2698; OMIM: 149200
Name:
Autosomal dominant nonsyndromic hearing loss 3A
Synonyms:
Deafness, autosomal dominant 3a
Identifiers:
MONDO: MONDO:0011103; MedGen: C2675750; Orphanet: 90635; OMIM: 601544

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003920013Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Dec 10, 2021) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV003920013.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

GJB2 NM_004004.5 exon 2 p.Leu90Pro (c.269T>C): This variant has been reported in the literature in the homozygous or compound heterozygous state in several individuals with nonsyndromic hearing loss (D'Andrea 2002 PMID:12176036, Tekin 2003 PMID:14738110, Zoll 2003 PMID:12497637, Azaiez 2004 PMID:15365987, Mikstiene 2016 PMID:26896187, Likar 2018 PMID:29293505, Prasad 2018 PMID:29554876). This variant is also present in 0.1% (153/129066) of European alleles in the Genome Aggregation Database https://gnomad.broadinstitute.org/variant/13-20763452-A-G). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:17016). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant through impairment of gap junction channel assembly and function (D'Andrea 2002 PMID:12176036, Bruzzone 2003 PMID:12505163, Palmada 2006 PMID:16300957). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024