rs776749939
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP3_ModeratePP5BS2
The NM_003900.5(SQSTM1):c.1160C>T(p.Pro387Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P387A) has been classified as Uncertain significance.
Frequency
Consequence
NM_003900.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SQSTM1 | NM_003900.5 | c.1160C>T | p.Pro387Leu | missense_variant | 7/8 | ENST00000389805.9 | |
SQSTM1 | NM_001142298.2 | c.908C>T | p.Pro303Leu | missense_variant | 8/9 | ||
SQSTM1 | NM_001142299.2 | c.908C>T | p.Pro303Leu | missense_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SQSTM1 | ENST00000389805.9 | c.1160C>T | p.Pro387Leu | missense_variant | 7/8 | 1 | NM_003900.5 | P1 | |
SQSTM1 | ENST00000360718.5 | c.908C>T | p.Pro303Leu | missense_variant | 6/7 | 1 | |||
SQSTM1 | ENST00000510187.5 | c.950+550C>T | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251090Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135770
GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461822Hom.: 1 Cov.: 33 AF XY: 0.0000358 AC XY: 26AN XY: 727212
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74302
ClinVar
Submissions by phenotype
Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2014 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 11, 2018 | The P387L variant in the SQSTM1 gene has been reported in individuals with Paget disease of bone as well as inindividuals with frontotemporal dementia (Johnson-Pais et al., 2003; Gennari et al., 2010; Le Ber et al., 2013; vander Zee et al., 2014). In vitro studies demonstrate that the P387L results in decreased binding of monoubiquitin andpolyubiquitin as compared to wild-type (Cavey et al., 2006). The P387L variant was not observed in approximately6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating itis not a common benign variant in these populations. The P387L variant is a semi-conservative amino acidsubstitution, which may impact secondary protein structure as these residues differ in some properties and occurs at aposition that is conserved across species. The P387L variant is a strong candidate for a pathogenic variant, howeverthe possibility it may be a rare benign variant cannot be excluded. - |
Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 387 of the SQSTM1 protein (p.Pro387Leu). This variant is present in population databases (rs776749939, gnomAD 0.03%). This missense change has been observed in individual(s) with Paget disease, frontotemporal dementia or dementia (PMID: 14584883, 20200946, 22972638, 24042580, 24899140, 25796131, 29525180). ClinVar contains an entry for this variant (Variation ID: 202211). 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 expected to disrupt SQSTM1 protein function. Experimental studies have shown that this missense change affects SQSTM1 function (PMID: 16691492, 17229008). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at