Submissions for variant NM_001167.4(XIAP):c.478A>G (p.Met160Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002300406	SCV002594156	uncertain significance	X-linked lymphoproliferative disease due to XIAP deficiency	2023-03-02	criteria provided, single submitter	clinical testing	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 expected to disrupt XIAP protein function. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 160 of the XIAP protein (p.Met160Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with XIAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 1721417). 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.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV002300406	SCV005397584	uncertain significance	X-linked lymphoproliferative disease due to XIAP deficiency	2024-02-05	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (A>G) at position 478 of the coding sequence of the XIAP gene that results in a methionine to valine amino acid change at residue 160 of the X-linked inhibitor of apoptosis protein. This residue falls in the Baculoviral inhibition of apoptosis protein repeat 2 (UniProt) which plays a critical role in protein function. This is a previously reported variant (ClinVar 1721417) that has not been observed in the literature in individuals affected by XIAP-related disease, to our knowledge. This variant is absent from the gnomAD v4.0.0 population database (0/~1209000 alleles). Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Met160 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP3, PP4