Submissions for variant NM_000397.4(CYBB):c.1414G>A (p.Gly472Ser)

gnomAD frequency: 0.00018  dbSNP: rs13306300

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000907309	SCV001052005	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	RCV002307640	SCV002600598	benign	not specified	2022-10-20	criteria provided, single submitter	clinical testing	Variant summary: CYBB c.1414G>A (p.Gly472Ser) results in a non-conservative amino acid change located in the Ferric reductase, NAD binding domain (IPR013121) 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 0.00084 in 204242 control chromosomes (gnomAD), with 48 hemizygotes. The variant occurs predominantly at a frequency of 0.011 within the East Asian subpopulation in the gnomAD database, including 45 hemizygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYBB causing X-Linked Chronic Granulomatous Disease (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Fulgent Genetics, Fulgent Genetics	RCV002502710	SCV002801189	likely benign	X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency; Granulomatous disease, chronic, X-linked	2022-04-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003413719	SCV004118286	uncertain significance	CYBB-related disorder	2023-06-12	criteria provided, single submitter	clinical testing	The CYBB c.1414G>A variant is predicted to result in the amino acid substitution p.Gly472Ser. This variant has been reported in male patients with X-linked chronic granulomatous disease and respiratory phenotypes (Patient 85, Chiu et al. 2021. PubMed ID: 35140711; Table S2, Patient 100, Dai et al. 2021. PubMed ID: 34134972). It has also been reported in a female patient with pneumonia, lymphadenitis, allergic rhinitis, maxillary sinusitis, adenoid hypertrophy, acanthosis nigricans, moderate anemia, EBV infection (Patient 17, Wu et al. 2017. PubMed ID: 28251166). This variant is reported in 1.1% of alleles in individuals of East Asian descent in gnomAD, including 45 hemizygotes in that subpopulation (http://gnomad.broadinstitute.org/variant/X-37665739-G-A), which may be too common to be causative. This variant is also reported as likely benign/benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/732210/). However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV003438571	SCV004164800	benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	CYBB: BS1, BS2
Natera, Inc.	RCV001832042	SCV002087151	benign	Chronic granulomatous disease	2020-01-21	no assertion criteria provided	clinical testing