ClinVar Genomic variation as it relates to human health

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Reported in individuals with ALS and in unaffected controls (Fecto et al., 2011; Shimizu et al., 2013; van der Zee et al., 2014; Cady et al., 2015; Cuyvers et al., 2015; Morgan et al., 2017; Yilmaz et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26234378, 35240373, 28166811, 25796131, 32594029, 31859009, 34009082, 23812289, 24899140, 22084127, 27275741, 28430856, 25382069)

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 153 of the SQSTM1 protein (p.Val153Ile). This variant is present in population databases (rs145056421, gnomAD 0.04%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 22084127, 23812289, 24899140, 25796131, 31859009). ClinVar contains an entry for this variant (Variation ID: 571746). 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 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.

This sequence change in SQSTM1 is predicted to replace valine with isoleucine at codon 153, p.(Val153Ile). The valine residue is weakly conserved (100 vertebrates, UCSC), and is located in the zinc finger domain. There is a small physicochemical difference between valine and isoleucine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.042% (54/128,964 alleles) in the European (non-Finnish) population. This variant has been reported in individuals with amyotrophic lateral sclerosis (PMID: 22084127, 23812289). Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.161). 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: BP4

Variant summary: SQSTM1 c.457G>A (p.Val153Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251200 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SQSTM1 causing SQSTM1-Related Disorders, allowing no conclusion about variant significance. c.457G>A has been reported in the literature in individuals affected with Amyotrophic lateral sclerosis as well as unaffected controls (e.g. Fecto_2011, Shimizu_2013, van der Zee_2014, Yilmaz_2020). These reports do not provide unequivocal conclusions about association of the variant with SQSTM1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22084127, 23812289, 24899140, 31859009). ClinVar contains an entry for this variant (Variation ID: 571746). Based on the evidence outlined above, the variant was classified as uncertain significance.

The SQSTM1 c.457G>A variant is predicted to result in the amino acid substitution p.Val153Ile. This variant has been reported in an individual with amyotrophic lateral sclerosis (ALS) who also carried an additional missense variant in SQSTM1 in trans (Shimizu et al. 2013. PubMed ID: 23812289) and has been observed in other patients with ALS (Table 1, Yilmaz et al. 2019. PubMed ID: 31859009; Fecto et al. 2011. PubMed ID: 22084127). In another study, this variant was found in one patient with ALS, but also observed in three controls (Table 2, van der Zee et al. 2014. PubMed ID: 24899140). In a large ALS case-control study, the c.457G>A variant was reported in one healthy control but not in any individuals with ALS (Morgan et al. 2017. PubMed ID: 28430856). This variant has also been observed in an individual with glaucoma and an individual with Alzheimer disease, but was also observed in otherwise healthy controls in both studies (Scheetz et al. 2016. PubMed ID: 27275741; Table 1, Cuyvers et al. 2015. PubMed ID: 25796131). This variant is reported in 0.042% of alleles in individuals of European (non-Finnish) descent in gnomAD, which is likely too common for a fully penetrant autosomal dominant variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.