ClinVar Miner

Submissions for variant NM_001540.5(HSPB1):c.418C>G (p.Arg140Gly) (rs121909112)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000688660 SCV000816282 pathogenic Charcot-Marie-Tooth disease type 2F 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 140 of the HSPB1 protein (p.Arg140Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the heterozygous state in multiple individuals affected with Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) (PMID: 18832141, 27816334). It has also been reported in the homozygous state in an individual affected with distal vacuolar myopathy and motor neuropathy (PMID: 28702508). ClinVar contains an entry for this variant (Variation ID: 7484). Experimental studies have shown that this missense change leads to mitochondrial dysfunction and decreased HSPB1 thermal stability (PMID: 28595321, 23643870). For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000688660 SCV000999000 pathogenic Charcot-Marie-Tooth disease type 2F 2019-08-27 criteria provided, single submitter clinical testing A heterozygous missense variation in the exon 2 of the HSPB1 gene that results in the amino acid substitution of Glycine for Arginine at codon 140 was detected. The observed variant c.418C>G (p.Arg140Gly) has not been reported in 1000 genomes and ExAC databases. The in silico predictions of the variant are damaging by SIFT, LRT and MutationTaster2. The observed variant has previously been reported in patients affected with Charcot-Marie-Tooth disease type 2 (Holden et al 2008 Neurology). Furthermore, functional studies have shown that the said variant affects the quaternary structure and decreases the chaperon like activity of the protein (Nefedova et al 2013 Biochimie). In summary, the said variant meets our criteria to be classified as pathogenic.
OMIM RCV000007912 SCV000028117 pathogenic Distal hereditary motor neuronopathy type 2B 2008-11-18 no assertion criteria provided literature only

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