ClinVar Miner

Submissions for variant NM_001540.5(HSPB1):c.539C>G (p.Thr180Ser)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000807584 SCV000947646 uncertain significance Charcot-Marie-Tooth disease type 2F 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 180 of the HSPB1 protein (p.Thr180Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with clinical features of Charcot-Marie-Tooth disease type 2 (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Thr180 amino acid residue in HSPB1. Another variant that disrupts this residue has been observed in individuals with HSPB1-related conditions (PMID: 27862672, 20870250, 22176143, 28144995), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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