ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.491G>A (p.Arg164Gln) (rs1241595912)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000654841 SCV000776743 pathogenic Charcot-Marie-Tooth Neuropathy X 2020-06-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 164 of the GJB1 protein (p.Arg164Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Charcot-Marie-Tooth disease, type 1X (PMID: 9187667, 25025039, 23106488, 10923043, 12497641, 22243284, 15241803, 11571214, 26454100, 27027447). ClinVar contains an entry for this variant (Variation ID: 543920). Experimental studies have shown that this missense change creates a connexin 32 protein with impaired channel permeability that does not localize to the plasma membrane properly (PMID: 27844031). A different missense substitution at this codon (p.Arg164Trp) has been determined to be pathogenic (PMID: 9187667, 15006706, 27027447, 27025386, 7580242). This suggests that the arginine residue is critical for GJB1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001310733 SCV001500643 pathogenic not provided 2020-09-01 criteria provided, single submitter clinical testing
GeneDx RCV001310733 SCV001818519 pathogenic not provided 2020-10-22 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, including reduced plasma membrane expression of GJB1 and GJ plaque formation combined with predominant cytoplasmic retention of GJB1, and impaired GJ permeability (Tsai et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31948496, 32022442, 31211173, 22243284, 27027447, 27025386, 15006706, 27844031, 14663027, 9361298, 15241803, 27544631, 20443038, 25025039, 17100997, 11571214, 10923043, 9854984, 26454100, 23649551, 18379723, 12497641, 10737979, 10220155, 27098783, 9187667, 7580242)
Inherited Neuropathy Consortium RCV000789839 SCV000929223 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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