Submissions for variant NM_000397.4(CYBB):c.1551T>A (p.Asp517Glu)

gnomAD frequency: 0.00144  dbSNP: rs151344452

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000059246	SCV000511098	likely benign	not provided	2016-11-02	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083190	SCV000762327	benign	Granulomatous disease, chronic, X-linked	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781320	SCV000919255	benign	not specified	2018-12-04	criteria provided, single submitter	clinical testing	Variant summary: CYBB c.1551T>A (p.Asp517Glu) results in a conservative amino acid change located in the Ferric reductase, NAD binding domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 193905 control chromosomes, including 75 hemizygous males, predominantly at a frequency of 0.0021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in CYBB causing X-linked Chronic Granulomatous Disease phenotype (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.1551T>A, has been reported in the literature in one individual affected with X-linked Chronic Granulomatous Disease as a benign variant, together with c.90C>A (p.Y30X)(Hill_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV000059246	SCV005209220	likely benign	not provided		criteria provided, single submitter	not provided
UniProtKB/Swiss-Prot	RCV000059246	SCV000090775	not provided	not provided		no assertion provided	not provided
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000059246	SCV001797759	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000781320	SCV001974049	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003964915	SCV004794308	likely benign	CYBB-related disorder	2020-09-22	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).