Submissions for variant NM_004004.6(GJB2):c.132G>A (p.Trp44Ter)

gnomAD frequency: 0.00008  dbSNP: rs104894407

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146007	SCV000193158	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000593364	SCV000700809	pathogenic	not provided	2016-12-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000593364	SCV000883945	pathogenic	not provided	2017-05-09	criteria provided, single submitter	clinical testing	The GJB2 c.132G>A; p.Trp44Ter variant (rs104894407) has been reported in the literature in individuals with hearing loss who carried a pathogenic variant on the opposite chromosome (Green 1999, Martinez-Saucedo 2015, Roux 2004). It is reported in ClinVar (Variation ID: 158605), and observed in the general population databases at a frequency of 0.003 percent (8/276604 alleles; Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript, and is considered pathogenic. REFERENCES Link to ClinVar database for p.Trp44Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/158605/ Green GE et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999 Jun 16;281(23):2211-6. Martinez-Saucedo M et al. Two novel compound heterozygous families with a trimutation in the GJB2 gene causing sensorineural hearing loss. Int J Pediatr Otorhinolaryngol. 2015 Dec;79(12):2295-9. Roux AF et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004 Mar 6;5:5.
Invitae	RCV000593364	SCV000933879	pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp44*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894407, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 10376574, 15070423, 26346709, 26553399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 158605). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Leu56Argfs*26) have been determined to be pathogenic (PMID: 15967879, 16380907, 21465647, 22695344, 24158611). 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	RCV000593364	SCV001168433	pathogenic	not provided	2021-11-05	criteria provided, single submitter	clinical testing	Observed with a pathogenic variant in additional unrelated patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Green et al., 1999; Roux et al., 2004; Angeli et al., 2008); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 183 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 17666888, 26553399, 18758381, 10376574, 31589614, 15070423, 26346709, 17041943, 34440441)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984267	SCV002051360	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-12-24	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.132G>A (p.Trp44X) 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 3.5e-05 in 258564 control chromosomes. c.132G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (example, Green_1999, Prasad_2000, Snoeckx_2005, Roux_2004, Tang_2006, Putcha_2007, Lin_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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.
Genomics and Human Genetics Laboratory, Pasteur Institut of Morocco	RCV000984267	SCV004023237	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A		criteria provided, single submitter	clinical testing
Counsyl	RCV000984267	SCV001132398	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2015-03-06	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000984267	SCV001453353	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing