Submissions for variant NM_001540.5(HSPB1):c.407G>T (p.Arg136Leu)

dbSNP: rs863225022

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000201072	SCV000255780	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2015-07-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000236739	SCV000292874	pathogenic	not provided	2024-07-15	criteria provided, single submitter	clinical testing	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: 32334137, 32301006, 26989944, 25547330, 24607769, Scalia2021[Review], 34129932, 31902012, 33943041, 22176143, 21611841, 33973728, 38968664, 37170966)
Ambry Genetics	RCV000622699	SCV000741123	pathogenic	Inborn genetic diseases	2015-11-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201072	SCV000832663	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 136 of the HSPB1 protein (p.Arg136Leu). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individuals with clinical features of Charcot-Marie-Tooth disease type 2 and distal hereditary motor neuropathy (PMID: 21611841, 22176143, 25547330, 26989944). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217230). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HSPB1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg136 amino acid residue in HSPB1. Other variant(s) that disrupt this residue have been observed in individuals with HSPB1-related conditions (PMID: 15122254, 20178975, 22521462), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000789060	SCV001337300	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000236739	SCV002563957	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000201072	SCV005395951	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2024-10-07	criteria provided, single submitter	clinical testing	This missense variant has been reported multiple times as pathogenic or likely pathogenic in ClinVar. It has been reported in patients presenting with Charcot-Marie-Tooth, type 2 (OMIM # 606595) (PMID 25547330). This variant is not present in genome population database gnomAD (v4.1.0). Based on the evidence outlined above, the variant was classified as pathogenic.
Inherited Neuropathy Consortium	RCV000789060	SCV000928409	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only