Submissions for variant NM_032444.4(SLX4):c.2585G>A (p.Arg862Gln)

gnomAD frequency: 0.00030  dbSNP: rs143558209

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000764060	SCV000396860	uncertain significance	Fanconi anemia complementation group P	2018-01-12	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.
Invitae	RCV000260361	SCV000626411	uncertain significance	Fanconi anemia	2022-08-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 862 of the SLX4 protein (p.Arg862Gln). This variant is present in population databases (rs143558209, gnomAD 0.08%). 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: 319165). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics, Fulgent Genetics	RCV000764060	SCV000895014	uncertain significance	Fanconi anemia complementation group P	2022-03-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000764060	SCV003823926	uncertain significance	Fanconi anemia complementation group P	2019-12-04	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000764060	SCV003920493	uncertain significance	Fanconi anemia complementation group P	2022-07-07	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in association with disease. This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.09% [38/41460]; https://gnomad.broadinstitute.org/variant/16-3591053-C-T?dataset=gnomad_r3), and is present in ClinVar, with multiple laboratories classifying it as of uncertain significance (Variation ID:319165). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV003391154	SCV004118848	uncertain significance	SLX4-related disorder	2023-09-06	criteria provided, single submitter	clinical testing	The SLX4 c.2585G>A variant is predicted to result in the amino acid substitution p.Arg862Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3641054-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.