Submissions for variant NM_004004.6(GJB2):c.647_650del (p.Arg216fs)

dbSNP: rs587783647

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146027	SCV000193181	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000153313	SCV000227312	pathogenic	not provided	2015-03-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217521	SCV000271228	likely pathogenic	Rare genetic deafness	2015-06-08	criteria provided, single submitter	clinical testing	The p.Arg216fs variant in GJB2 has been previously reported in one individual wi th hearing loss who was compound heterozygous for a second pathogenic variant in GJB2 (Prasad 2000, variant reported as c.645_648delTAGA). This variant was abse nt from large population studies, though the ability of these studies to accurat ely detect indels may be limited. This variant is predicted to cause a frameshif t, which alters the protein?s amino acid sequence beginning at position 216 and leads to a new termination codon 17 amino acids downstream, thus resulting in a longer protein (the abnormal protein is 5 amino acids longer than the normal pro tein). This variant is expected to disrupt the normal function of the protein; h owever additional data is needed to confirm this. In summary, although additiona l studies are required to fully establish its clinical significance, the p.Arg21 6fs variant is likely pathogenic based on its presence in compound heterozygosit y with a known pathogenic variant in an affected individual and the predicted im pact to the protein.
Counsyl	RCV000175766	SCV000487633	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-06-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000411907	SCV000487634	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-06-21	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000175766	SCV000599765	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000153313	SCV000613522	pathogenic	not provided	2015-07-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987374	SCV000698270	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-01-09	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.647_650delGATA (p.Arg216IlefsX17) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 4.8e-05 in 250054 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (4.8e-05 vs 0.025), allowing no conclusion about variant significance. c.647_650delGATA has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (examples: Prasad_2000, Tang_2006, Putcha_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11102979, 17666888, 17041943). ClinVar contains an entry for this variant (Variation ID: 158609). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000153313	SCV000709969	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein elongation, as the last 11 amino acids are replaced with 16 different amino acids.; This variant is associated with the following publications: (PMID: 15365987, 17041943, 11102979, 25288386, 31160754, 17666888)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000153313	SCV001158549	pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing	The GJB2 c.647_650delGATA; p.Arg216IlefsTer17 variant (rs587783647), also known as c.645_648delTAGA, is reported in the literature in the compound heterozygous state in multiple individuals affected with autosomal-recessive nonsyndromic hearing loss (Azaiez 2004, Hernandez-Juarez 2014, Prasad 2000, Putcha 2007, Tang 2006). This variant is reported as pathogenic or likely pathogenic by multiple laboratories in ClinVar (Variation ID: 158609), and is found in the Latino population with an allele frequency of 0.035% (12/34560 alleles) in the Genome Aggregation Database. This variant results in a premature termination codon in the last exon of the GJB2 gene. While this may not lead to nonsense-mediated decay, it is expected to create an altered protein that would include a sequence of 17 amino acid residues not usually present. Furthermore, functional analyses show that small deletions or additions to the C-terminus of the protein affect channel function (Locke 2011). Based on available information, this variant is considered to be pathogenic. References: Azaiez H et al. GJB2: the spectrum of deafness-causing allele variants and their phenotype. Hum Mutat. 2004 Oct;24(4):305-11. Hernandez-Juarez AA et al. GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico. Int J Pediatr Otorhinolaryngol. 2014 Dec;78(12):2107-12. Locke D et al. Mechanism for modulation of gating of connexin26-containing channels by taurine. J Gen Physiol. 2011 Sep;138(3):321-39. Prasad S et al. Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA). Hum Mutat. 2000 Dec;16(6):502-8. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Tang HY et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006 Nov 15;140(22):2401-15.
Invitae	RCV000153313	SCV001206581	pathogenic	not provided	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg216Ilefs*17) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs587783647, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with autosomal recessive sensorineural deafness (PMID: 11102979, 17041943, 17666888, 25288386). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.645-648delTAGA. ClinVar contains an entry for this variant (Variation ID: 158609). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266307	SCV001444480	likely pathogenic	Inborn genetic diseases	2018-08-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000153313	SCV002024249	pathogenic	not provided	2019-06-25	criteria provided, single submitter	clinical testing