Submissions for variant NM_000397.4(CYBB):c.1498G>T (p.Asp500Tyr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003332534	SCV004039843	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18546332, 15577746, 29560547)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003509811	SCV004299775	pathogenic	Granulomatous disease, chronic, X-linked	2023-06-16	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 500 of the CYBB protein (p.Asp500Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with chronic granulomatous disease (PMID: 18546332, 29560547). In at least one individual the variant was observed to be de novo. 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 CYBB protein function. This variant disrupts the p.Asp500 amino acid residue in CYBB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18546332, 22125116; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.