Submissions for variant NM_001110219.3(GJB6):c.228del (p.Trp77fs)

gnomAD frequency: 0.00003  dbSNP: rs751484173

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001038857	SCV001202356	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B; Autosomal dominant nonsyndromic hearing loss 3B; Hidrotic ectodermal dysplasia syndrome	2023-04-15	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 837505). This premature translational stop signal has been observed in individual(s) with non-syndromic hearing loss (PMID: 29771057, 35062939). This variant is present in population databases (rs751484173, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This sequence change creates a premature translational stop signal (p.Trp77Glyfs*5) in the GJB6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 185 amino acid(s) of the GJB6 protein.
GeneDx	RCV001759946	SCV001990671	uncertain significance	not provided	2021-04-29	criteria provided, single submitter	clinical testing	Observed in a patient with palmoplantar keratosis in published literature (Banerjee et al., 2015); however, this variant did not segregate with disease in additional family members; Observed with a GJB2 variant in a patient with nonsyndromic hearing loss in published literature (Yu et al., 2020); Frameshift variant predicted to result in protein truncation, as the last 185 amino acids are replaced with four different amino acids, 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: 29771057, 25429721, 31992338)