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

gnomAD frequency: 0.00001  dbSNP: rs770272088

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204495	SCV000260941	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2024-05-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 84 of the HSPB1 protein (p.Gly84Arg). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease or distal hereditary motor neuropathy (dHMN) (PMID: 18344398, 18832141, 21892769, 25429913). ClinVar contains an entry for this variant (Variation ID: 220419). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HSPB1 protein function. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 18344398, 23948568). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000992169	SCV001144218	pathogenic	not provided	2019-03-12	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease, and data include affected and unaffected individuals from multiple families.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000789334	SCV001337296	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000992169	SCV002520034	pathogenic	not provided	2022-10-04	criteria provided, single submitter	clinical testing	PP3, PS1, PS3, PS4_moderate
Ambry Genetics	RCV002426966	SCV002744256	likely pathogenic	Inborn genetic diseases	2019-09-03	criteria provided, single submitter	clinical testing	The p.G84R variant (also known as c.250G>C), located in coding exon 1 of the HSPB1 gene, results from a G to C substitution at nucleotide position 250. The glycine at codon 84 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple patients with neuropathy in both heterozygous and homozygous states and has been functionally studied and shown to result in a defective protein. (Houlden H et al. Neurology, 2008 Nov;71:1660-8; James PA et al. J. Neurol. Neurosurg. Psychiatry, 2008 Apr;79:461-3; Fischer C et al. J. Neurol., 2012 Mar;259:515-23; Nefedova VV et al. Arch. Biochem. Biophys., 2013 Oct;538:16-24; Manganelli F et al. J. Peripher. Nerv. Syst., 2014 Dec;19:292-8; Ho CC et al. Int J Mol Sci, 2017 Apr;18:(4). pii: E770). The same amino acid change has been reported in the literature resulting from a different nucleotide substitution, c.250G>A (Manganelli F et al. J. Peripher. Nerv. Syst., 2014 Dec;19:292-8; Ho CC et al. Int J Mol Sci, 2017 Apr;18:(4). pii: E770). Based on data from gnomAD, the C allele has an overall frequency of approximately 0.0007% (1/147494). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV003993892	SCV004812353	pathogenic	Distal hereditary motor neuropathy type 2	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in HSPB1 is predicted to replace glycine with arginine at codon 84, p.(Gly84Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in the N-terminal region. There is a large physicochemical difference between glycine and arginine. This variant is present in a single European (non-Finnish) individual in gnomAD v2.1 (1/60,362 alleles). This variant has been reported in at least six probands with hereditary motor neuropathies, and segregates with disease in at least two families (PMID: 18344398, 18832141, 21892769, 27816334; Shariant). Expression of the variant in heterologous systems showed protein aggregate formation, altered protein oligomerisation, and decreased charperone-like acitivty indicating that this variant impacts protein function (PMID: 18344398, 23948568). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). The same amino acid change (p.Gly84Arg), resulting from a different nucleotide change c.250G>A, is classified as likely pathogenic for hereditary motor neuropathy (ClinVar ID: 632006). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS1, PS4_Moderate, PS3_Supporting, PM2_Supporting, PP1, PP3.
GeneDx	RCV000992169	SCV005324948	likely pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	Identified in a homozygous state in a patient with severe Charcot Marie Tooth disease whose heterozygous parents were more mildly affected with impaired tendon reflexes (PMID: 21892769); Published functional studies demonstrate a damaging effect on protein stability and ability to form large heterooligomers (PMID: 23948568), as well as enhanced cytoplasmic aggregation of the mutant protein (PMID: 18344398); Reported in patients with distal hereditary motor neuropathy in published literature (PMID: 18832141, 18344398, 27816334); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32528171, 28000086, 32334137, 28797631, 18344398, 34128983, 27816334, 31573509, 18832141, 21892769, 23948568)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786551	SCV005398838	pathogenic	Neuronopathy, distal hereditary motor, type 2B	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with axonal Charcot-Marie-Tooth disease type 2F (MIM#606595) and distal hereditary motor neuronopathy 3 (MIM#608634) (PMID: 25220807). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (33 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This missense variant (and also c.250G>A) has multiple pathogenic reports in unrelated individuals (ClinVar, LOVD). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Inherited Neuropathy Consortium	RCV000789334	SCV000928687	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only