ClinVar

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 392 of the SQSTM1 protein (p.Pro392Leu). This variant is present in population databases (rs104893941, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Paget disease of the bone (PMID: 11473345, 11992264, 15125799, 17229007). It has also been observed to segregate with disease in related individuals. The penetrance of this variant appears to be reduced and increases with age. In one study, the penetrance was 50% across all age groups but 17% below the age of 50 (PMID: 17229007). Of note, this variant has also been observed in individuals with frontotemporal dementia (PMID: 24899140, 24042580), amyotrophic lateral sclerosis (PMID:23417734, 23942205, 24899140, 28430856), and myopathy (PMID:29457785, 29599744), but the association with these diseases is unclear. ClinVar contains an entry for this variant (Variation ID: 8108). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SQSTM1 protein function. Experimental studies have shown that this missense change affects SQSTM1 function (PMID: 15765181, 16813535, 19589897, 21195346, 21878516). For these reasons, this variant has been classified as Pathogenic.