Submissions for variant NM_003900.5(SQSTM1):c.962G>A (p.Arg321His)

gnomAD frequency: 0.00006  dbSNP: rs752889531

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817686	SCV000958263	uncertain significance	Frontotemporal dementia and/or amyotrophic lateral sclerosis 1; Paget disease of bone 2, early-onset	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 321 of the SQSTM1 protein (p.Arg321His). This variant is present in population databases (rs752889531, gnomAD 0.01%). This missense change has been observed in individual(s) with SQSTM1-related conditions (PMID: 24042580, 24899140, 31859009). ClinVar contains an entry for this variant (Variation ID: 660485). 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.
Illumina Laboratory Services, Illumina	RCV001155512	SCV001316946	uncertain significance	Paget disease of bone 3	2017-04-28	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). 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.
GeneDx	RCV001779082	SCV002015502	uncertain significance	not provided	2024-12-05	criteria provided, single submitter	clinical testing	Observed in individuals with frontotemporal dementia in the published literature (PMID: 24042580, 24899140); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24899140, 31859009, 24042580, 33770234)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252249	SCV002522777	uncertain significance	See cases	2021-08-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004540116	SCV004773125	uncertain significance	SQSTM1-related disorder	2024-01-22	no assertion criteria provided	clinical testing	The SQSTM1 c.962G>A variant is predicted to result in the amino acid substitution p.Arg321His. This variant was reported in individuals with frontotemporal lobar degeneration (Le Ber et al. 2013. PubMed ID: 24042580; van der Zee et al. 2014. PubMed ID: 24899140) and amyotrophic lateral sclerosis (Yilmaz et al. 2019. PubMed ID: 31859009; Vacchiano et al. 2021. PubMed ID: 34020145). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.