ClinVar Miner

Submissions for variant NM_001540.5(HSPB1):c.404C>A (p.Ser135Tyr) (rs28939680)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000641078 SCV000762696 pathogenic Charcot-Marie-Tooth disease type 2F 2018-01-15 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 135 of the HSPB1 protein (p.Ser135Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with distal hereditary motor neuropathy and Charcot-Marie-Tooth disease (PMID: 27816334, 23963299, Invitae) and has been reported to segregate with Charcot-Marie-Tooth disease in a single family (PMID: 23963299). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). A different missense substitution at this codon (p.Ser135Phe) has been determined to be pathogenic (PMID: 15122254, 18832141, 17881652). This suggests that the serine residue is critical for HSPB1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Inherited Neuropathy Consortium RCV000789965 SCV000929351 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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