ClinVar Miner

Submissions for variant NM_000101.4(CYBA):c.203+5G>A

gnomAD frequency: 0.00026  dbSNP: rs200590340
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000642287 SCV000763956 uncertain significance Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative 2022-09-13 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the CYBA gene. It does not directly change the encoded amino acid sequence of the CYBA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200590340, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CYBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 534660). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003987638 SCV004804387 uncertain significance not specified 2024-01-11 criteria provided, single submitter clinical testing Variant summary: CYBA c.203+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 244146 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CYBA causing Chronic Granulomatous Disease (0.00024 vs 0.00061), allowing no conclusion about variant significance. c.203+5G>A has been reported in the literature in one individual affected with Chronic Granulomatous Disease (Sacco_2019). The 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. The following publication have been ascertained in the context of this evaluation (PMID: 31813112). ClinVar contains an entry for this variant (Variation ID: 534660). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001271488 SCV001452677 uncertain significance Chronic granulomatous disease 2019-10-28 no assertion criteria provided clinical testing

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