ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.88A>G (p.Ile30Val)

gnomAD frequency: 0.00004  dbSNP: rs374625633
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672312 SCV000797409 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2018-01-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002298731 SCV002598766 uncertain significance not specified 2022-09-28 criteria provided, single submitter clinical testing Variant summary: GJB2 c.88A>G (p.Ile30Val) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250470 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (4.4e-05 vs 0.00034), allowing no conclusion about variant significance. c.88A>G has been reported in the literature as a non-informative genotype (second allele not specified) in individuals affected with deafness of variable etiology (example, Hwa_2003, Roesch_2018, Gallego-Martinez_2019, Xie_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss/GJB2-associated hearing loss. At-least one report of its identification as a heterozygous genotype in an individual with co-occurring compound heterozygous pathogenic variant(s) in the SLC26A4 gene, indicating a diagnosis of Pendred syndrome (Xie_2021, SLC26A4 c.919-2A>G; SLC26A4 c.1229C>T, p.Thr410Met), provides supporting evidence for a benign role (alternate molecular basis of disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Fulgent Genetics, Fulgent Genetics RCV002493110 SCV002797741 uncertain significance 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 2021-12-18 criteria provided, single submitter clinical testing

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