ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.6729+5_6729+19del (rs749526785)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497773 SCV000589300 likely pathogenic not provided 2016-09-20 criteria provided, single submitter clinical testing The c.6729+5_6729+19del15 variant has been reported in association with ABCA4-related eye disorders (Littink et al., 2010; Fujinami et al. 2013; Duncker et al., 2015). Upon examining the phenotypes and ages-of-onset associated with different variants, it was observed that the c.6729+5_6729+19del15 variant is associated with a very early age-of-onset with the median age-of-onset being 5 years (Fakin et al., 2016). The c.6729+5_6729+19del15 variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.6729+5_6729+19del15 either damages or destroys the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is a likely pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000497773 SCV000700938 pathogenic not provided 2017-05-23 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074704 SCV001240297 pathogenic Retinal dystrophy 2019-04-03 criteria provided, single submitter clinical testing
Invitae RCV000497773 SCV001392513 pathogenic not provided 2019-11-17 criteria provided, single submitter clinical testing This sequence change falls in intron 48 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein, but it affects a nucleotide within the consensus splice site of the intron. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with bullseye maculopathy (PMID: 25283059), autosomal recessive retinitis pigmentosa (PMID: 28041643), retinal degeneration (PMID: 27583828), cone-rod dystrophy (PMID: 20554613), and Stargardt disease (PMID: 29925512). This variant is also known as c.6729+4del15 in the literature. ClinVar contains an entry for this variant (Variation ID: 283573). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 29162642). For these reasons, this variant has been classified as Pathogenic.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000416441 SCV000494173 pathogenic Cone-rod dystrophy 3 no assertion criteria provided research This variant was identified as homozygous in an individual with cone rod dystrophy.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504933 SCV000599022 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000678515 SCV000804587 uncertain significance Retinitis pigmentosa 19 2016-09-01 no assertion criteria provided clinical testing

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