ClinVar Miner

Submissions for variant NM_000433.4(NCF2):c.366+1G>A

gnomAD frequency: 0.00001  dbSNP: rs796065032
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522170 SCV000617713 pathogenic not provided 2016-08-19 criteria provided, single submitter clinical testing The c.366+1 G>A splice site variant in the NCF2 gene has been previously reported in association with chronic granulomatous disease (CGD) (Patiño et al., 1999). In vitro functional studies demonstrated that the expression level of the mutant RNA was less than 5% in comparison to a normal control (Patiño et al., 1999). Furthermore, three different cDNAs were observed, two missing at least one exon and one with a deletion of the last 5 nucleotides of exon 4, which is expected to result in a frameshift variant (Patiño et al., 1999). The c.366+1 G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This pathogenic variant destroys the canonical splice donor site in intron 3, and is expected to cause abnormal gene splicing.
Labcorp Genetics (formerly Invitae), Labcorp RCV000002331 SCV000937524 pathogenic Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 2022-07-25 criteria provided, single submitter clinical testing Disruption of this splice site has been observed in individual(s) with chronic granulomatous disease (PMID: 10498624, 20167518). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in several alternate splicing products and introduces a premature termination codon (PMID: 10498624). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 2243). This variant is also known as intron 4 +1G>A. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the NCF2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
OMIM RCV000002331 SCV000022489 pathogenic Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 1999-10-01 no assertion criteria provided literature only

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