ClinVar Miner

Submissions for variant NM_001540.5(HSPB1):c.116C>T (p.Pro39Leu) (rs557327165)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000641079 SCV000762697 pathogenic Charcot-Marie-Tooth disease axonal type 2F 2019-02-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 39 of the HSPB1 protein (p.Pro39Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to segregate with autosomal dominant Charcot Marie Tooth disease in several families (PMID: 28144995, 27816334, 18832141, 22176143). This variant has also been reported in several other individuals affected with Charcot Marie Tooth disease including at least one individual in whom the variant appeared to arise de novo (PMID: 28144995, 29381233). ClinVar contains an entry for this variant (Variation ID: 533814). Experimental studies have shown that this missense change causes mitochondrial dysfunction, increased aggregation, increased resistance to dissociation, and decreased chaperone-like activity of HSPB1 (PMID: 25965061, 28595321). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory,London Health Sciences Centre RCV000789058 SCV001337299 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197515 SCV001368291 pathogenic Pes cavus; Motor axonal neuropathy; Distal peripheral sensory neuropathy 2019-01-24 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PS1. This variant was detected in heterozygous state.
Inherited Neuropathy Consortium RCV000789058 SCV000928407 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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