Submissions for variant NM_001540.5(HSPB1):c.407G>T (p.Arg136Leu) (rs863225022)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000201072	SCV000255780	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2015-07-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000236739	SCV000292874	likely pathogenic	not provided	2016-02-03	criteria provided, single submitter	clinical testing	The R136L variant has been reported previously in association with CMT2 and dHMN in two unrelated individuals (Capponi et al., 2011) and with CMT2F/dHMN in multiple affected family members (Stancanelli et al., 2014). Additionally, a different amino acid substitution at the same position (R136W) and many nearby missense variants have been published in association with HSPB1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R136L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R136L variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species, and in silico analysis predicts this substitution is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic
Ambry Genetics	RCV000622699	SCV000741123	pathogenic	Inborn genetic diseases	2015-11-23	criteria provided, single submitter	clinical testing
Invitae	RCV000201072	SCV000832663	pathogenic	Charcot-Marie-Tooth disease axonal type 2F	2019-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with leucine at codon 136 of the HSPB1 protein (p.Arg136Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with features of Charcot-Marie-Tooth, type 2 (CMT2) disease and distal hereditary motor neuropathy (dHMN) in affected families (PMID: 25547330, 21611841). This variant has also been reported in additional, unrelated individuals affected with CMT2 and dHMN (PMID: 22176143, 26989944). ClinVar contains an entry for this variant (Variation ID: 217230). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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, 22521462, 20178975), 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
Inherited Neuropathy Consortium	RCV000789060	SCV000928409	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only