ClinVar Miner

Submissions for variant NM_001110219.3(GJB6):c.31G>A (p.Gly11Arg) (rs104894415)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000005882 SCV000198189 pathogenic Hidrotic ectodermal dysplasia syndrome 2014-02-01 criteria provided, single submitter clinical testing The p.Gly11Arg variant in GJB6 is one of the four pathogenic variant associated with hidrotic ectodermal dysplasia 2 (Clouston syndrome, HED2) and has been repo rted in >10 individuals with HED2 and segregated with disease in >30 affected fa mily members (Chen 2010, Common 2002, Fujimoto 2013, Lamartine 2000). In additi on, this variant has not been identified in large population studies. In summary , this variant meets our criteria to be classified as pathogenic (http://www.par tners.org/personalizedmedicine/LMM).
GeneDx RCV000255581 SCV000321729 pathogenic not provided 2016-08-03 criteria provided, single submitter clinical testing The G11R missense pathogenic variant in the GJB6 gene has been reported previously in Clouston syndrome patients of French-Canadian, Spanish, African, and French ancestry (Tiedemann et al., 2014; Lamartine et al., 2000). G11R is one of the most common GJB6 pathogenic variants and affects the amino-terminal tail domain of the gap junction protein connexin 30. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The missense change is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Another substitution at the same nucleotide (c.31 G>C) that also leads to the G11R misssense change has been reported in the Human Gene Mutation Database in association with Clouston syndrome (Stenson et al., 2014), supporting the functional importance of this residue of the protein. In addition, functional studies have shown that G11R results in impaired trafficking in vitro and is overcome by interaction with other connexins during in vivo study (Di et al., 2005).
Invitae RCV000645727 SCV000767480 pathogenic Deafness, autosomal recessive 1A; Deafness, autosomal recessive 1b; Deafness, autosomal dominant 3b; Hidrotic ectodermal dysplasia syndrome 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 11 of the GJB6 protein (p.Gly11Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with ectodermal dysplasia in multiple families (PMID: 11017065, 12788524, 23981984, 23926005, 24514865, 26551294, 27817781). ClinVar contains an entry for this variant (Variation ID: 5544). Experimental studies, in vitro, have shown that this missense change impairs trafficking to the plasma membrane and results in abnormal hemichannel activity (PMID: 12419304, 15213106, 15769851). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762909 SCV000893319 pathogenic Deafness, autosomal recessive 1A; Deafness, autosomal recessive 1b; Deafness, autosomal dominant 3b; Deafness, X-linked 2; Hidrotic ectodermal dysplasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000005882 SCV000026064 pathogenic Hidrotic ectodermal dysplasia syndrome 2000-10-01 no assertion criteria provided literature only

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