ClinVar Miner

Submissions for variant NM_001540.5(HSPB1):c.165_171dup (p.Leu58fs) (rs748762287)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522999 SCV000620838 uncertain significance not provided 2017-10-04 criteria provided, single submitter clinical testing The c.165_171dupGCGCCCC variant in the HSPB1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This frameshift variant replaces the typical last 148 amino acid residues in the HSPB1 protein with 104 different amino acid residues. This change is expected to alter the normal structure and function of the resultant protein. The c.165_171dupGCGCCCC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.165_171dupGCGCCCC as a variant of uncertain significance
Invitae RCV001213209 SCV001384830 likely pathogenic Charcot-Marie-Tooth disease axonal type 2F 2019-07-15 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the HSPB1 gene (p.Leu58Alafs*105). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 148 amino acids of the HSPB1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual affected with Charcot-Marie-Tooth disease (PMID: 28144995). ClinVar contains an entry for this variant (Variation ID: 452063). Variants that disrupt the region between p.Pro39 and p.Gln175 are associated with autosomal dominant HSPB1-related conditions (PMID: 28144995, 29381233, 22734906, 28144995). As this variant disrupts this region, this suggests that it is likely to be clinically significant. 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.

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