ClinVar Miner

Submissions for variant NM_012106.4(ARL2BP):c.207+1G>A

gnomAD frequency: 0.00005  dbSNP: rs199830550
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001857201 SCV002229487 pathogenic not provided 2023-10-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the ARL2BP gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs199830550, gnomAD 0.04%). Disruption of this splice site has been observed in individuals with inherited retinal dystrophy (PMID: 27790702, 28041643, 30210231, 32581362). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 437946). Studies have shown that disruption of this splice site results in skipping of exon 3 and introduces a premature termination codon (PMID: 30210231). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003392337 SCV004120146 pathogenic ARL2BP-related condition 2023-05-25 criteria provided, single submitter clinical testing The ARL2BP c.207+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous state in individuals with retinal dystrophy (Patient G005193 in Table S2, Carss et al. 2017. PubMed ID: 28041643; Fiorentino et al. 2018. PubMed ID: 30210231; Supplementary Table 2 in Turro et al. 2020. PubMed ID: 32581362). This variant was reported in the homozygous state in a male patient with retinal pigmentosa and abnormal sperm morphology (P1 in Moye et al. 2019. PubMed ID: 31425546). Functional studies showed that this variant led to skipping of exon 3 (Fiorentino et al. 2018. PubMed ID: 30210231; Moye et al. 2019. PubMed ID: 31425546). This variant is reported in 0.049% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-57282556-G-A). Variants that disrupt the consensus splice donor site in ARL2BP are expected to be pathogenic. This variant is interpreted as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504888 SCV000598678 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research

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