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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