ClinVar Miner

Submissions for variant NM_001540.5(HSPB1):c.250G>C (p.Gly84Arg) (rs770272088)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204495 SCV000260941 pathogenic Charcot-Marie-Tooth disease type 2F 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 84 of the HSPB1 protein (p.Gly84Arg). 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 was reported in several families affected with CMT2 or distal hereditary motor neuropathy (dHMN). Currently there is insufficient evidence to conclude whether this variant segregates with disease or not in these families (PMID: 18344398, 18832141, 21892769, 25429913). ClinVar contains an entry for this variant (Variation ID: 220419). Experimental studies have shown that this missense change disrupts the stability of both HSPB1 homo-oligomeric and HSPB1/HSPB6 hetero-oligomeric protein complexes (PMID: 18344398, 23948568). HSPB1-Gly84Arg proteins were also found to have decreased chaperone-like activity when tested on model substrates (PMID: 23948568). In summary, this variant has been identified in multiple individuals affected with CMT but not the general population, and functional studies have suggested that it interferes with HSPB1 protein function. For these reasons, it has been classified as Pathogenic.
Inherited Neuropathy Consortium RCV000789334 SCV000928687 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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