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

dbSNP: rs756484720

Total submissions: 11

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 Inc	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	2016-06-09	criteria provided, single submitter	clinical testing	The p.Lys112fs variant in GJB2 has been reported in eight individuals with heari ng loss (Kelley 1998, Wu 2002, Putcha 2007, Nishio 2015). One of these individua ls and their sibling were compound heterozygous for this variant and a second pa thogenic GJB2 variant (Kelley 1998). This variant is predicted to cause a frames hift, which alters the protein?s amino acid sequence beginning at position 112 a nd leads to a premature termination codon 2 amino acids downstream. This alterat ion 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 hea ring loss. In summary, this variant meets the criteria to be classified as patho genic for autosomal recessive hearing loss based on its presence in compound het erozygosity with a known pathogenic variant in an affected individual and the pr edicted impact of the variant.
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.
Invitae	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	2022-04-12	criteria provided, single submitter	clinical testing	Observed in other patients with hearing loss in published literature (Putcha et al., 2007; Dodson et al., 2011; Atik et al., 2015); Frameshift variant predicted to result in protein truncation, as the last 115 amino acids are lost and replaced with 1 incorrect amino acid, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database; This variant is associated with the following publications: (PMID: 31215297, 26561413, 27177978, 23141775, 9529365, 26990548, 21465647, 25587757, 22695344, 17666888, 12172394, 29257206, 27941975, 33096615, 31589614)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222422	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
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