ClinVar Miner

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

dbSNP: rs104894409
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Total submissions: 14
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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for the variant, and segregated in 3 affected siblings wi th hearing loss (Cryns 2004, Kelley 1998, Kenna 2001, LMM Unpublished data).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.
Invitae 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 2023-06-15 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on biochemical permeability, while ionic coupling is intact (Zhang et al., 2005); 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, 16217030, 9529365, 17666888, 12189487, 11556849, 31160754, 33096615, 31589614, 34308104, 31331740)
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.
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

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