ClinVar Miner

Submissions for variant NM_003900.5(SQSTM1):c.1175C>T (p.Pro392Leu) (rs104893941)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824803 SCV000245666 pathogenic Spastic paraplegia-Paget disease of bone syndrome 2018-10-09 criteria provided, single submitter clinical testing The p.Pro392Leu variant in SQSTM1 has been reported in at least 100 individuals with Paget disease of the bone (PDB) and was found to segregate with PDB in >40 individuals across 11 families (Laurin 2002, Morissette 2006, Seton 2016). In vi tro and in vivo functional studies support an impact on protein function (Layfie ld 2004, Hiruma 2008, Chamoux 2009, Kurihara 2011; Daroszewska 2018); however, s ome of these studies suggest that the variant is not sufficient to cause disease on its own, and that environmental stimuli may play a role in its phenotypic ex pression (Hiruma 2008, Kurihara 2011). This variant has also been identified in 0.14% (179/126230) of European chromosomes by gnomAD, including 2 homozygous ind ividuals ( This appreciable frequency is consi stent with the reduced penetrance of PDB as well as the high prevalence of PDB i n European populations (estimates range from 0.2-10% across different patient po pulations; Morrisette 2006, Valenzuela 2017). It should be noted that this varia nt has also been reported in patients with frontotemporal dementia (FTD; van der Zee 2014, Le Ber 2013), amyotrophic lateral sclerosis (ALS; Teyssou 2013, Kwok 2014, van der Zee 2014, Morgan 2017), and myopathy (Lee 2018, Niu 2018). However , the role of the SQSTM1 gene in these disorders is not well established. In sum mary, the p.Pro392Leu variant meets criteria to be classified as pathogenic for PDB in an autosomal dominant manner with reduced penetrance. Additional data is required to determine if this variant contributes to other disorders.
Illumina Clinical Services Laboratory,Illumina RCV000008576 SCV000456921 pathogenic Paget disease of bone 3 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.
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.
Invitae RCV001084507 SCV000774416 benign Amyotrophic lateral sclerosis and/or frontotemporal dementia 1; Paget disease of bone 2, early-onset 2019-12-31 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000008576 SCV001428461 pathogenic Paget disease of bone 3 2019-04-29 criteria provided, single submitter clinical testing
OMIM RCV000008576 SCV000028784 pathogenic Paget disease of bone 3 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
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477939 SCV000536745 likely pathogenic Paget disease of bone 3; Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 2016-06-23 no assertion criteria provided research

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