Submissions for variant NM_000433.4(NCF2):c.1184G>A (p.Arg395Gln)

gnomAD frequency: 0.00131  dbSNP: rs145229115

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000526980	SCV000351757	uncertain significance	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526980	SCV000641906	likely benign	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2	2025-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001701989	SCV002504085	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	Reported in individuals with inflammatory bowel disease in published literature (PMID: 29454792, 32463623); 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: 24163247, 34547651, 29454792, 32463623)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000526980	SCV003920268	likely benign	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2	2022-10-13	criteria provided, single submitter	clinical testing	This variant has been reported in association with Crohn's disease and inflammatory bowel disease (Denson 2018 PMID: 29454792; Ashton 2020 PMID: 32463623). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.2% [140/68026]; https://gnomad.broadinstitute.org/variant/1-183563301-C-T?dataset=gnomad_r3). It is also present in ClinVar, with several laboratories classifying it as benign or likely benign (Variation ID: 2248). Evolutionary conservation and computational predictive tools strongly suggest that this variant does not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003417936	SCV004118601	uncertain significance	NCF2-related disorder	2023-09-08	criteria provided, single submitter	clinical testing	The NCF2 c.1184G>A variant is predicted to result in the amino acid substitution p.Arg395Gln. This variant has been reported in association with inflammatory bowel disease (Table 1, Denson et al. 2018. PubMed ID: 29454792; Table 2, Ashton et al. 2020. PubMed ID: 32463623). However, this variant is reported in 0.20% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-183532436-C-T), which may be too high to be causative. This variant also has conflicting interpretations regarding its pathogenic in ClinVar, ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/294080/). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701989	SCV001930145	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001701989	SCV001966914	likely benign	not provided		no assertion criteria provided	clinical testing