Submissions for variant NM_000265.7(NCF1):c.75_76del (p.Tyr26fs)

dbSNP: rs4029402

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001090891	SCV001246653	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	NCF1: PVS1, PM2
GeneDx	RCV001090891	SCV001985174	pathogenic	not provided	2020-03-27	criteria provided, single submitter	clinical testing	Is the most common cause of autosomal recessive chronic granulomatous disease (CGD); has a carrier frequency of 1:250 in the population (Leiding et al., 2012); Accounts for more than 95% of pathogenic variants in the NCF1 gene (Noack et al., 2001); Arises from a recurrent gene conversion event between NCF1 and flanking pseudogenes containing the dinucleotide deletion (Leiding et al., 2012); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; No reliable data available from control populations to assess the frequency of this variant as the variant is pseudogene-derived; This variant is associated with the following publications: (PMID: 22138397, 22876374, 10706888, 2011585, 26409780, 27699571, 27699569, 27701760, 28130637, 29560547, 11133775, 8147881, 30651282, 30470980, 30409207, 30319683, 31631731, 31482473, 31813112, 32040803, 33365035)
Molecular Genetics, Royal Melbourne Hospital	RCV000002337	SCV002503741	pathogenic	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change is a deletion of 2 bp in exon 2 (of 11) of NCF1 that is predicted to create a premature termination codon at position 51, p.(Tyr26Hisfs*26). It is expected to result in nonsense-mediated decay, and loss of function is an established mechanism of disease for this gene (PVS1; ClinVar). The variant does not pass quality control in the gnomAD dataset, and thus cannot be assessed for population frequency (gnomAD v2.1, v3.0). Homozygosity of this variant is the most common cause of chronic granulomatous disease (CGD) due to deficiency of NCF1, produced by a recombination event between NCF1 & pseudogenes (PMID: 9329953). It has been identified in the homozygous and to a lesser degree compound heterozygous state with a second pathogenic allele in multiple CGD cases, and segregation with disease has been reported in over 12 families (PM3_VeryStrong, PP1_Strong; examples in PMID: 11133775, 16972229, 21190454). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PP1_Strong.
Baylor Genetics	RCV000002337	SCV005049772	pathogenic	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1	2023-12-13	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000002337	SCV005438378	pathogenic	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1	2024-12-18	criteria provided, single submitter	clinical testing
OMIM	RCV000002337	SCV000022495	pathogenic	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1	2001-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000002337	SCV000054520	pathologic	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1	2012-08-09	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	RCV002283438	SCV002573423	pathogenic	Granulomatous disease, chronic, X-linked	2022-05-01	no assertion criteria provided	clinical testing