Submissions for variant NM_004004.6(GJB2):c.250G>C (p.Val84Leu)

dbSNP: rs104894409

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211770	SCV000061492	pathogenic	Rare genetic deafness	2017-06-22	criteria provided, single submitter	clinical testing	The p.Val84Leu variant in GJB2 has been reported in 7 individuals with hearing l oss, 6 of whom were compound heterozygous for a second pathogenic variant and 1 of whom was homozygous for the variant, and segregated in 3 affected siblings wi th hearing loss (Cryns 2004, Kelley 1998, Kenna 2001, LMM Unpublished data). Thi s variant was identified in 4/33580 Latino chromosomes; however, this frequency is low enough to be consistent with a recessive carrier frequency. Functional st udies indicate that the Val84Leu variant compromises connexin 26 protein functio n (Beltramello 2005). In summary, this variant meets criteria to be classified a s pathogenic for autosomal recessive hearing loss based on the previously report ed individuals, segregation data, and low frequency in the general population.
Genetic Services Laboratory, University of Chicago	RCV000146012	SCV000193163	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000018560	SCV000599740	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000018560	SCV000698239	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-02-22	criteria provided, single submitter	clinical testing	Variant summary: The GJB2 c.250G>C (p.Val84Leu) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 3/4 in silico tools (SNPs&GO not captured due to low reliability index). The Val84 is proposed to be at the membrane-spanning segments M2/M3 helix interface of the GJB2 protein (Ambrosi_2010). This variant was found in 8/121696 control chromosomes from ExAC at a frequency of 0.0000657, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is widely reported as a pathogenic variant in literature and is found in ARNSHL patients in homozygous as well as in compound heterozygous state with other known pathogenic variants, including evidence of cosegregation with disease (Kelley_1998, Azaiez_2004, Snoeckx_2005, Zoll_2002, Dalamon_2013, Dahl_2013). Multiple functional studies show that although the V84L mutant channels are able to make gap junctions in mammalian and insect cells, stable in detergent solution and able to allow passage of simple ions (such as LY), they do not allow permeability for molecules larger than simple ions (such as propidium iodide) and reduce permeability to the Ca2+-mobilizing messenger inositol 1,4,5-trisphosphate (Bruzzone_2003, Wang_2003, Beltramello_2005, Zhang_2005, Ambrosi_2010). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Another missense variant at this residue p.V84M has been classified as pathogenic by our lab and others in ClinVar. Taken together, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001041795	SCV001205435	pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Leu). This variant is present in population databases (rs104894409, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 11556849, 12172394, 16380907, 19235794, 24013081, 26346709). ClinVar contains an entry for this variant (Variation ID: 17032). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 12505163, 12562518, 15592461, 16217030, 20441744). For these reasons, this variant has been classified as Pathogenic.
INGEBI, INGEBI / CONICET	RCV001257042	SCV001433547	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.250G>C, p.Val84Leu has a filtering allele frequency of 0.00395% in Latino population from Genome Aggregation Database v2.1.1 (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/) meeting PM2 criteria. Computational analysis predicted a pathogenic effect of the variant to the protein (REVELscore=0.947) applying to PP3 rule. This variant was identified in trans with at least 5 known pathogenic variants meeting PM3_VeryStrong criteria (PMID: 24158611, 95239365, 11556849,12172394, 12189487,12497637, 14985372, 15365987, 17041943). The p.Val84Leu change in trans with a pathogenic variant segregated in two affected siblings in a family case. (PP1_Supporting; PMID: 95239365). Dye transfer and electrical coupling assays demonstrated that the variant do not impact the protein function (PMID: 12505163, 12562518, 16217030). However, some assays showed a reduce permeability to IP3 and intracellular exchange of large molecules (PMID: 12505163, 16217030), and therefore this evidence was not counted. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss (PM2, PP3, PM3_VeryStrong and PP1_Supporting).
Athena Diagnostics	RCV001041795	SCV001476374	pathogenic	not provided	2021-05-26	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant results in impaired permeability to larger molecules, such as inositol 1,4,5-trisphosphate (PMID: 15592461, 16217030). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
GeneDx	RCV001041795	SCV001770240	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on biochemical permeability, while ionic coupling is intact (PMID: 16217030); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17426645, 24158611, 23555729, 15365987, 25087612, 25388846, 15592461, 16380907, 14985372, 12562518, 12505163, 20441744, 9529365, 17666888, 12189487, 31160754, 33096615, 31589614, 34308104, 31331740, 11556849, 16217030)
Fulgent Genetics, Fulgent Genetics	RCV002504805	SCV002808981	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	2021-10-08	criteria provided, single submitter	clinical testing
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	RCV000018560	SCV003935272	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-06-02	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335046	SCV004046406	pathogenic	GJB2-related disorder		criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous or homozygous variant in individuals with congenital hearing impairment (PMID: 16380907, 26346709, 24013081, 19235794, 11556849, 12172394, 12189487, 12497637, 15365987). Functional studies have shown that this missense change affects biochemical permeability and intercellular transport of large molecules (PMID: 12505163, 12562518, 15592461, 20441744, 16217030). The c.250G>C (p.Val84Leu) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (9/251338) and is absent in the homozygous state, thus is presumed to be rare. In silico analyses predict a deleterious effect of the c.250G>C (p.Val84Leu) variant on protein function. Based on the available evidence, the c.250G>C (p.Val84Leu) variant is classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001041795	SCV005198028	pathogenic	not provided	2023-07-12	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000018560	SCV005399536	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to leucine. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 9 heterozygotes, 0 homozygotes). An alternative nucleotide change to adenine resulting in the same protein change is also present in gnomAD (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Val84Met) has been reported multiple times as pathogenic in ClinVar. (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The same nucleotide change, as well as the alternative change to adenine, have been reported in compound heterozygote and homozygote individuals with deafness (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000018560	SCV000038842	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2005-01-01	no assertion criteria provided	literature only
Counsyl	RCV000018560	SCV001132401	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-11-13	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000018560	SCV002086057	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-12-18	no assertion criteria provided	clinical testing