Submissions for variant NM_004004.6(GJB2):c.334_335del (p.Lys112fs)

dbSNP: rs756484720

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169446	SCV000220865	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2014-11-07	criteria provided, single submitter	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000169446	SCV000599745	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000517108	SCV000613513	pathogenic	not provided	2017-06-19	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000616234	SCV000710860	pathogenic	Rare genetic deafness	2019-08-27	criteria provided, single submitter	clinical testing	The p.Lys112fs variant in GJB2 has been reported in eight individuals with hearing loss (Kelley 1998, Wu 2002, Putcha 2007, Nishio 2015). One of these individuals and their sibling were compound heterozygous for this variant and a second pathogenic GJB2 variant (Kelley 1998). The p.Lys112fs variant has also been identified in 0.002% (1/34582) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 112 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GJB2 gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PVS1, PM2, PM3, PP1.
INGEBI, INGEBI / CONICET	RCV001257562	SCV001434016	pathogenic	Nonsyndromic genetic hearing loss	2020-08-21	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.334_335del variant which leads to p.(Lys112Glufs*2) in the GJB2 gene is present in only 1/34582 Latino alleles in Genome Aggregation Database (http://gnomad.broadinstitute.org); meeting the PM2 criteria. The c.334_335del variant is predicted to cause a premature stop codon in the only exon of GJB2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant was detected in trans with 2 different pathogenic or suspected pathogenic variants in at least 4 hearing loss patients (PMID: 9529365, 21465647, 22695344, 23141775) applying to PM3_VeryStrong. Two familial cases with two affected siblings in each one showed segregation of the genotypes: c.[334_335del];[35delG] and c.[334_335del];[638T>A] in the affected siblings respectively applying to PP1_Moderate rule (PMID: 9529365, 23141775) In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2, PVS1, PM3_VeryStrong, PP1_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000517108	SCV001590824	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys112Glufs*2) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs756484720, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 9529365, 23141775). It has also been observed to segregate with disease in related individuals. This variant is also known as c.333-334delAA. ClinVar contains an entry for this variant (Variation ID: 189051). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Gln124*) have been determined to be pathogenic (PMID: 9600457). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000517108	SCV001829601	pathogenic	not provided	2024-08-27	criteria provided, single submitter	clinical testing	Reported in association with hearing loss in additional cases in published literature (PMID: 21465647, 17666888, 26561413); however, patient clinical information limited or not provided; Frameshift variant predicted to result in abnormal protein length as the last 115 amino acids are replaced with 1 different amino acid, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 31215297, 26561413, 27177978, 23141775, 9529365, 26990548, 25587757, 22695344, 17666888, 12172394, 29257206, 27941975, 33096615, 31589614, 34599368, 24158611, 15954104, 21465647)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169446	SCV002500583	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-03-22	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.334_335delAA (p.Lys112GlufsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250258 control chromosomes. c.334_335delAA has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss, and has been shown to segregate with disease in several families. Seven 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498844	SCV002807439	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2021-11-18	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000169446	SCV005051795	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-02-01	criteria provided, single submitter	curation
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678879	SCV000805072	pathogenic	Hearing loss	2013-03-21	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169446	SCV001453337	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing