ClinVar Miner

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

dbSNP: rs756484720
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Total submissions: 10
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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 (; 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 2021-11-07 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.
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

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