ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201072 SCV000255780 pathogenic Charcot-Marie-Tooth disease 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 likely pathogenic Inborn genetic diseases 2015-11-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000201072 SCV000832663 likely pathogenic Charcot-Marie-Tooth disease type 2F 2018-07-03 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 a phenotype with features of Charcot-Marie-Tooth, type 2 (CMT2) disease and distal hereditary motor neuropathy (dHMN) in a family (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"). The observation of one or more missense substitutions at this codon (p.Arg136Leu and p.Arg136Trp) in affected individuals suggests that this may be a clinically significant residue (PMID: 15122254, 22176143). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Inherited Neuropathy Consortium RCV000789060 SCV000928409 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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