Submissions for variant NM_003900.5(SQSTM1):c.50C>T (p.Ala17Val)

gnomAD frequency: 0.00004  dbSNP: rs141502868

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001155397	SCV001316823	uncertain significance	Paget disease of bone 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001238678	SCV001411504	uncertain significance	Frontotemporal dementia and/or amyotrophic lateral sclerosis 1; Paget disease of bone 2, early-onset	2024-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 17 of the SQSTM1 protein (p.Ala17Val). 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. This missense change has been observed in individual(s) with frontotemporal lobardegeneration (FTLD) (PMID: 24899140). ClinVar contains an entry for this variant (Variation ID: 906314). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SQSTM1 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV001267032	SCV001445213	uncertain significance	Inborn genetic diseases	2018-07-28	criteria provided, single submitter	clinical testing
GeneDx	RCV003236871	SCV003935717	uncertain significance	not provided	2023-06-22	criteria provided, single submitter	clinical testing	Previously reported in an individual with FTLD, and in a control individual (van der Zee et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8650207, 24899140)
Molecular Genetics, Royal Melbourne Hospital	RCV003994220	SCV004812350	uncertain significance	Frontotemporal dementia and/or amyotrophic lateral sclerosis 3	2023-09-04	criteria provided, single submitter	clinical testing	This sequence change in SQSTM1 is predicted to replace alanine with valine at codon 17, p.(Ala17Val). The alanine residue is weakly conserved (100 vertebrates, UCSC), and is located in the PB1 domain in a region, amino acids 15-17, that is highly intolerant to missense variation (PMID: 31116477). There is a moderate physicochemical difference between alanine and valine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (6/107,756 alleles) in the European (non-Finnish) population. This variant has been reported in at least one individual with frontotemporal lobar degeneration (PMID: 24899140). Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.073). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM1, BP4.