Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000796950 | SCV000936485 | uncertain significance | Charcot-Marie-Tooth disease axonal type 2F | 2022-03-18 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 27 of the HSPB1 protein (p.Arg27Leu). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HSPB1 protein function. ClinVar contains an entry for this variant (Variation ID: 643281). This missense change has been observed in individual(s) with clinical features of HSPB1-related conditions (PMID: 32334137; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002298775 | SCV002598716 | uncertain significance | not specified | 2022-09-12 | criteria provided, single submitter | clinical testing | Variant summary: HSPB1 c.80G>T (p.Arg27Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 235340 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.80G>T has been reported in the literature in one individual affected with amyotrophic lateral sclerosis. This report does not provide unequivocal conclusions about association of the variant with HSPB1-related disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |