Submissions for variant NM_032444.4(SLX4):c.1520G>A (p.Arg507Lys)

gnomAD frequency: 0.00003  dbSNP: rs762550449

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000353541	SCV000396876	uncertain significance	Fanconi anemia complementation group P	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001344487	SCV001538545	uncertain significance	Fanconi anemia	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with lysine at codon 507 of the SLX4 protein (p.Arg507Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs762550449, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with SLX4-related conditions. ClinVar contains an entry for this variant (Variation ID: 319176). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx	RCV001537098	SCV001753929	uncertain significance	not provided	2020-11-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003409498	SCV004113264	uncertain significance	SLX4-related disorder	2023-05-24	criteria provided, single submitter	clinical testing	The SLX4 c.1520G>A variant is predicted to result in the amino acid substitution p.Arg507Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3647543-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.