ClinVar Miner

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

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Total submissions: 2
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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 2019-11-29 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.
Inherited Neuropathy Consortium RCV000789839 SCV000929223 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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