ClinVar Miner

Submissions for variant NM_001540.5(HSPB1):c.523C>T (p.Gln175Ter) (rs863225023)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201127 SCV000255781 pathogenic Charcot-Marie-Tooth disease axonal type 2F 2014-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000236115 SCV000292583 likely pathogenic not provided 2018-07-25 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the HSPB1 gene. The Q175X nonsense variant has been previously reported to segregate with CMT2 in six affected family members (Rossor et al., 2012). This variant is predicted to cause loss of normal protein function through protein truncation as the last 31 amino acid residues are lost. The Q175X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, the Q175X variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000201127 SCV000640215 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.Gln175*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 31 amino acids of the HSPB1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Charcot-Marie-Tooth disease type 2 in a single family (PMID: 22734906). This variant has also been observed in several individuals and families affected with Charcot-Marie-Tooth disease (PMID: 28144995). ClinVar contains an entry for this variant (Variation ID: 217231). A different variant (c.522_523delinsCT) giving rise to the same protein effect observed here (p.Gln175*) has been determined to be pathogenic (Invitae), suggesting that deletion of this region of the HSPB1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Genesis Genome Database RCV000857186 SCV000999768 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research

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