Submissions for variant NM_000631.5(NCF4):c.172C>T (p.Arg58Cys)

gnomAD frequency: 0.00103  dbSNP: rs143532979

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595538	SCV000706945	benign	not specified	2017-04-03	criteria provided, single submitter	clinical testing
Invitae	RCV000968901	SCV001116385	benign	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3	2024-01-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001509096	SCV001715623	uncertain significance	not provided	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001509096	SCV002005578	likely benign	not provided	2021-02-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29969437, 32181279)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000595538	SCV002570850	benign	not specified	2022-07-01	criteria provided, single submitter	clinical testing	Variant summary: NCF4 c.172C>T (p.Arg58Cys) results in a non-conservative amino acid change located in the phox homology domain (IPR001683) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251398 control chromosomes (gnomAD), predominantly at a frequency of 0.0095 within the Latino subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 38-fold of the estimated maximal expected allele frequency for a pathogenic variant in NCF4 causing Chronic Granulomatous Disease (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge no penetrant association of c.172C>T has been reported in individuals affected with Chronic Granulomatous Disease; 5 homozygous individuals of Latino origin were reported by van de Geer_2018, two unrelated individuals that appeared to have a mild phenotype resembling atypical Granulomatous disease, and three unaffected siblings. At least one study evaluated the impact of the variant on protein function, but found little evidence of functional impairment (van de Geer_2018). Four assessments for this variant have been submitted to ClinVar after 2014. Three submitters classified the variant as benign/likely benign and one classified it as VUS. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003905544	SCV004726368	likely benign	NCF4-related condition	2019-12-19	criteria provided, single submitter	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).