Submissions for variant NM_001540.5(HSPB1):c.383A>G (p.Gln128Arg)

gnomAD frequency: 0.00003  dbSNP: rs558882005

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000705379	SCV000470064	likely benign	Charcot-Marie-Tooth disease axonal type 2F	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000678497	SCV000470065	benign	Neuronopathy, distal hereditary motor, type 2B	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Biochimie - Maladies Neurologiques Hereditaires, Hospices Civils de Lyon	RCV000678497	SCV000804564	likely pathogenic	Neuronopathy, distal hereditary motor, type 2B	2017-02-02	criteria provided, single submitter	clinical testing
Invitae	RCV000705379	SCV000834372	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 128 of the HSPB1 protein (p.Gln128Arg). This variant is present in population databases (rs558882005, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant HSPB1-related conditions (PMID: 28144995, 31069529; Invitae). ClinVar contains an entry for this variant (Variation ID: 360738). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HSPB1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 28144995). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172549	SCV001335610	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365422	SCV002624638	likely benign	Inborn genetic diseases	2021-12-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.