Submissions for variant NM_001167.4(XIAP):c.185G>A (p.Arg62Gln)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003402671	SCV004119002	uncertain significance	XIAP-related disorder	2022-08-26	criteria provided, single submitter	clinical testing	The XIAP c.185G>A variant is predicted to result in the amino acid substitution p.Arg62Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-123019697-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003624519	SCV004467309	uncertain significance	X-linked lymphoproliferative disease due to XIAP deficiency	2023-08-04	criteria provided, single submitter	clinical testing	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. 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 XIAP protein function. This variant has not been reported in the literature in individuals affected with XIAP-related conditions. This variant is present in population databases (rs755189208, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 62 of the XIAP protein (p.Arg62Gln).
Neuberg Centre For Genomic Medicine, NCGM	RCV003624519	SCV005044778	uncertain significance	X-linked lymphoproliferative disease due to XIAP deficiency		criteria provided, single submitter	clinical testing	The missense c.185G>A p.Arg62Gln variant in XIAP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Arg62Gln variant has allele frequency 0.002% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid change p.Arg62Gln in XIAP is predicted as conserved by PhyloP across 100 vertebrates. The amino acid Arg at position 62 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS.