Submissions for variant NM_001110219.3(GJB6):c.689dup (p.Asn230fs)

dbSNP: rs398124237

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155697	SCV000205407	uncertain significance	not specified	2014-05-06	criteria provided, single submitter	clinical testing	The Asn230fs variant in GJB6 has been identified in at least two other individua ls, one without clinical information and one with hearing loss (ClinVar and LMM unpublished data, respectively). In addition, this variant has been identified i n 0.1% (8/8254) of European American chromosomes by the NHLBI Exome sequencing p roject (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathog enic role. This variant is predicted to cause a frameshift, which alters the pro tein?s amino acid sequence beginning at position 230 and leads to a premature te rmination codon 11 amino acids downstream. This alteration may lead to a truncat ed and altered protein. However, the role of GJB6 variants in nonsyndromic heari ng loss is currently unknown. In summary, additional information is needed to de termine the clinical significance of this variant.
GeneDx	RCV000081460	SCV001813310	likely benign	not provided	2022-02-04	criteria provided, single submitter	clinical testing	Observed with no other GJB6 variant in a patient with presumed autosomal recessive hearing loss, and in a patient with hearing loss attributed to neonatal meningitis in published literature (Beck et al., 2015); Frameshift variant predicted to result in protein truncation as the last 32 amino acids are lost and replaced with 10 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 25621899, 34426522, 25214170)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854433	SCV002143405	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B; Autosomal dominant nonsyndromic hearing loss 3B; Hidrotic ectodermal dysplasia syndrome	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn230Lysfs*11) in the GJB6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the GJB6 protein. This variant is present in population databases (rs398124237, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with deafness (PMID: 25214170). This variant is also known as c.682insA, c.682- 683insA. ClinVar contains an entry for this variant (Variation ID: 95435). 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.
Eurofins Ntd Llc (ga)	RCV000081460	SCV000113391	pathogenic	not provided	2013-05-20	no assertion criteria provided	clinical testing	Frameshift mutation is of a type predicted to cause disease.