ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.-23+1G>A (rs80338940)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000418755 SCV000841702 pathogenic not provided 2017-10-25 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678858 SCV000805051 pathogenic Hearing loss 2017-08-14 no assertion criteria provided clinical testing
Counsyl RCV000018557 SCV000678079 pathogenic Deafness, autosomal recessive 1A 2015-09-11 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000018557 SCV000599720 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762908 SCV000893318 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Keratoderma palmoplantar deafness; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000418755 SCV000516861 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing The c.- 23+1G>A pathogenic variant in the GJB2 gene has been reported previously in associationwith autosomal recessive hearing loss (Denoyelle et al., 1999; Zeinali et al., 2015), including itspresence as a founder variant in the Yakut population of eastern Siberia (Barashkov et al., 2011).Audiologic evaluation of 40 Yakut patients with the homozygous c.-23+1G>A variant found 85% ofthese individuals to have predominantly symmetrical severe to profound hearing loss (Barashkov etal., 2011). This splice site variant destroys the canonical splice donor site in intron 1. Functionalstudies indicate that this variant disrupts splicing and results in no gene transcription (Shahin et al.,2002). We interpret c.-23+1G>A as a pathogenic variant.
GeneReviews RCV000018557 SCV000041037 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided literature only Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000146002 SCV000193153 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000018557 SCV000902315 pathogenic Deafness, autosomal recessive 1A 2019-02-26 no assertion criteria provided case-control
Integrated Genetics/Laboratory Corporation of America RCV000018557 SCV000698237 pathogenic Deafness, autosomal recessive 1A 2016-10-24 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.-23+1G>A variant (alternatively also known as IVS1+1G>A, -3170G>A, -3201G>A, -3179G>A, and -3172G>A) involves the alteration of the invariant splice donor site in intron 1. 5/5 splice prediction tools predict that this variant eliminates the 5' splicing donor site. The prediction result was confirmed by a functional study; RNA isolated from lymphocytes from the proband carrying c.-23-1G>A variant and subsequent sequencing of cDNA showed no transcript from this allele (Shahin_2002). This variant was found in 21/4256 control chromosomes at a frequency of 0.0049342, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported as one of the common pathogenic variants causing ARNSHL in literature with consistent genotype-phenotype data. The variant has also been postulated to originate from and to have a founder effect in central Asia (Barashkov_2011). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000418755 SCV000957075 pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the GJB2 gene. It does not directly change the encoded amino acid sequence of the GJB2 protein. This variant is present in population databases (rs80338940, gnomAD 0.016%). This variant has been observed to segregate with hearing loss in several families (PMID: 27481527, 21776002) and has been reported in several individuals from different ethnic groups affected with hearing loss (PMID: 10218527, 21776002, 24959830, 27843504, 24840842, 11935342). This variant is considered a founder mutation in the Yakut population (PMID: 21776002). This variant is also known as IVS1+1G>A and -3170G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 17029). Experimental studies have shown that this change disrupts splicing, resulting in no detectable mRNA product (PMID: 11935342). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000018557 SCV000223931 pathogenic Deafness, autosomal recessive 1A 2015-02-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211766 SCV000061468 pathogenic Rare genetic deafness 2014-01-03 criteria provided, single submitter clinical testing The c.-23+1G>A variant in GJB2 has been reported in many probands with hearing l oss (Denoyelle 1999, Shahin 2002, Sirmaci 2006, Yuan 2010, Barashkov 2011). Most of these probands were homozygous or compound heterozygous. In addition, functi onal studies have shown that this variant disrupts splicing, yielding no detecta ble mRNA (Shahin 2002). In summary, this variant meets our criteria to be classi fied as pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3
OMIM RCV000018557 SCV000038839 pathogenic Deafness, autosomal recessive 1A 2011-09-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.