Submissions for variant NM_000433.4(NCF2):c.1081A>T (p.Thr361Ser)

gnomAD frequency: 0.00169  dbSNP: rs147744729

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526618	SCV000641903	likely benign	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2	2024-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000526618	SCV001257653	benign	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2	2017-05-25	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000526618	SCV001468386	uncertain significance	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2	2021-12-08	criteria provided, single submitter	clinical testing	NCF2 NM_000433.3 exon 12 p.Thr361Ser (c.1081A>T): This variant has been reported in the literature in at least one individual with inflammatory bowel disease (Denson 2018 PMID:29454792). This variant is also present in 0.2% (333/128812) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-183532666-T-A) and is present in ClinVar (Variation ID:466297). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV001532089	SCV001747486	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001532089	SCV001820040	likely benign	not provided	2020-12-07	criteria provided, single submitter	clinical testing	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: 29454792)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282216	SCV002570596	likely benign	not specified	2022-07-01	criteria provided, single submitter	clinical testing	Variant summary: NCF2 c.1081A>T (p.Thr361Ser) results in a conservative amino acid change located in the PB1 domain (IPR000270) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251066 control chromosomes (gnomAD), predominantly at a frequency of 0.0027 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 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in NCF2 causing Chronic Granulomatous Disease (0.00061), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1081A>T has been reported in the literature in at least one heterozygous individual affected with inflammatory bowel disease without strong evidence for causality (Denson_2018). This report does not provide unequivocal conclusions about association of the variant with Chronic Granulomatous Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (benign n=1, likely benign n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000526618	SCV003813502	uncertain significance	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2	2021-09-20	criteria provided, single submitter	clinical testing