ClinVar Miner

Submissions for variant NM_003900.4(SQSTM1):c.1175C>T (p.Pro392Leu) (rs104893941)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477939 SCV000536745 likely pathogenic Paget disease of bone, familial; Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 2016-06-23 no assertion criteria provided research
GeneDx RCV000490214 SCV000576840 uncertain significance not provided 2018-02-22 criteria provided, single submitter clinical testing The P392L variant in the SQSTM1 gene has been reported previously in association with Paget disease of bone (PDB) (Laurin et al., 2002). It has also been reported in individuals with PDB as well as frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) (Teyssou et al., 2013; Le Ber et al., 2013; Almeida et al., 2016). The P392L variant is more commonly associated with PDB and is considered the most common variant associated with both familial and sporadic PDB (Almeida et al., 2016). Mice with the P394L variant in the murine sqstm1 gene (equivalent to the P392L variant in human SQSTM1) developed a skeletal disorder similar to PDB, supporting the association between this variant and PDB in humans (Daroszewska et al., 2011). However, other studies have demonstrated that the P392L variant may be insufficient on its own to cause PDB, and additional genetic and/or environmental factors may be required (Kurihara et al., 2011; Seton et al., 2016). The link between the P392L variant and the associations with ALS and FTD has not been well studied to date. The P392L variant is observed in 258/276,726 (0.09%) total alleles in large population cohorts and two individuals were reported to be homozygous (Lek et al., 2016). The P392L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution is located within the UBA domain of the protein and occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (P387L, P388S, E389Q, S397A) have been reported in the Human Gene Mutation Database in association with SQSTM1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret P392L as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000008576 SCV000456921 pathogenic Paget disease of bone, familial 2017-04-28 criteria provided, single submitter clinical testing The SQSTM1 c.1175C>T (p.Pro392Leu) missense variant is the most commonly observed SQSTM1 variant in individuals with Paget disease of bone (PDB) to date (Seton et al. 2016). Across a selection of the literature, the p.Pro392Leu variant has been identified in a homozygous state in four PDB patients and in a heterozygous state in 101 individuals with familial PDB and in 211 individuals with sporadic PDB (Laurin et al. 2002; Michou et al. 2003; Hocking et al. 2004; Lucas et al. 2005; Morissette et al. 2006; Chung et al. 2008; Rea et al. 2009; Visconti et al. 2010; Seton et al. 2016). Morissette et al. (2006) calculated the penetrance of this variant to be 50% among all age groups, and approximately 80% for individuals over the age of 60. The p.Pro392Leu variant was absent from 1186 controls but is reported at a frequency of 0.02404 in the Puerto Ricans from Puerto Rico population of the 1000 Genomes Project. This frequency is high but is consistent with the disease prevalence and reduced penetrance seen among younger individuals. Several studies identified a shared ancestral haplotype among most individuals carrying the p.Pro392Leu variant allele, indicating that the variant is likely a founder mutation in populations of Western European descent (Laurin et al. 2002; Lucas et al. 2005; Morissette et al. 2006; Chung et al. 2008; Rea et al. 2009). Functional studies demonstrated that the p.Pro392Leu variant disrupted protein interaction and reduced binding affinity for ubiquitin (Cavey et al. 2005; Rea et al. 2006; Chamoux et al. 2009; Kurihara et al. 2011; Sundaram et al. 2011). Based on the collective evidence, the p.Pro392Leu variant is classified as pathogenic for Paget disease of bone. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000652546 SCV000774416 benign Amyotrophic lateral sclerosis and/or frontotemporal dementia 1; Paget disease of bone 2, early-onset 2018-01-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000008576 SCV000245666 likely pathogenic Paget disease of bone, familial 2014-11-24 criteria provided, single submitter clinical testing The p.Pro392Leu variant in SQSTM1 has been reported in >25 individuals with Paget's disease of the bone and was found to segregate with disease in >10 individuals from 8 families (Laurin 2002). However, this variant has also been identified in 0.21% (18/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs10489394). Functional studies provide some evidence that the p.Pro392Leu variant impacts protein function (Layfield 2004, Hiruma 2008, Chamoux 2009, Kurihara 2011), however these types of assays may not accurately represent biological function. Recently, this variant has also been identified in patients with frontotemporal dementia (FTD; van der Zee 2014, Le Ber 2013) and amyotrophic lateral sclerosis (ALS; Teyssou 2013, Kwok 2014, van der Zee 2014); however the role of the SQSTM1 gene in these disorders is not well established. In summary, although additional studies are required to fully establish its clinical significance, the p.Pro392Leu variant is likely pathogenic for Paget's disease of the bone. While this variant has been described in individuals with FTD and ALS, additional data is required to determine if this variant contributes to these disorders.
OMIM RCV000008576 SCV000028784 pathogenic Paget disease of bone, familial 2014-09-01 no assertion criteria provided literature only
OMIM RCV000184063 SCV000236597 pathogenic Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 2014-09-01 no assertion criteria provided literature only

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