ClinVar Miner

Submissions for variant NM_001540.5(HSPB1):c.180dup (p.Ala61fs) (rs1064796370)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483555 SCV000573025 likely pathogenic not provided 2018-07-18 criteria provided, single submitter clinical testing The c.180dupC variant in the HSPB1 gene causes a frameshift starting with codon Alanine 61, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 100 of the new reading frame, denoted p.Ala61ArgfsX100. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 145 amino acids of the HSPB1 protein are lost and replaced with 99 incorrect amino acids. Multiple variants are noted in the last 145 amino acid residues of the HSPB1 protein in the Human Gene Mutation Database in association with HSPB1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Biochimie - Maladies Neurologiques Hereditaires,Hospices Civils de Lyon RCV000678496 SCV000804563 likely pathogenic Distal hereditary motor neuronopathy type 2B 2017-02-02 criteria provided, single submitter clinical testing
Invitae RCV001242069 SCV001415131 pathogenic Charcot-Marie-Tooth disease axonal type 2F 2019-10-21 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the HSPB1 gene (p.Ala61Argfs*100). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 145 amino acids of the HSPB1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in an individual affected with distal hereditary motor neuropathy (PMID: 28144995). ClinVar contains an entry for this variant (Variation ID: 423339). This variant disrupts the region of the HSPB1 protein between p.Pro39Leu and p.Pro182Ala. This region has been determined to be associated with autosomal dominant HSPB1-related conditions (PMID: 28144995, 29381233, 22734906), which suggests that variants that occur in this region are likely to be clinically significant. For these reasons, this variant has been classified as Pathogenic.

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