Submissions for variant NM_000350.3(ABCA4):c.4253+43G>A

gnomAD frequency: 0.00486  dbSNP: rs61754045

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199365	SCV001370464	uncertain significance	Age related macular degeneration 2	2019-08-21	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PS3.
Institute of Medical Molecular Genetics, University of Zurich	RCV001290208	SCV001548167	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000085618	SCV001887559	uncertain significance	not provided	2023-07-24	criteria provided, single submitter	clinical testing	Observed frequently in individuals with Stargardt disease (including late-onset forms), inherited retinal degeneration, and age-related macular degeneration without another ABCA4 variant or phase unknown with other ABCA4 variant(s) (Fujinami et al., 2019; Zhu et al., 2022; Del Pozo-Valero et al., 2022; Nassisi et al., 2019; Runhart et al., 2019; Zernant et al., 2018; Sangermano et al., 2019 and others); Compared to individuals with classic Stargardt disease, affected individuals compound heterozygous for this variant were reported to have a milder phenotype, often with foveal sparing and a later onset of symptoms in the fifth to sixth decade (Zernant et al., 2018; Sangermano et al., 2019; Lee et al., 2022); Located within intron 28, outside the exon-intron boundaries; In vitro assay suggests c.4253+43G>A may cause skipping of exon 28 in a percentage of cells (Sangermano et al., 2019; Runhart et al., 2019), while in silico analysis indicates this nucleotide substitution has no predicted effect on splicing and is not conserved across species; In silico analysis supports that this variant does not alter splicing; Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 36209838, 31212395, 35353811, 29925512, 31618761, 35456422, 35055178, 34874912, 35119454, 31614660, 32619608, 32307445, 32278709, 33214125, 32531858, 33020556, 31963381, 34440443, 33546218, 30670881, 29848554, 30643219)
CeGaT Center for Human Genetics Tuebingen	RCV000085618	SCV002544293	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Very Strong, PM2:Supporting, PS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV003415862	SCV004115433	likely pathogenic	ABCA4-related condition	2023-08-02	criteria provided, single submitter	clinical testing	The ABCA4 c.4253+43G>A variant is predicted to interfere with splicing. This variant has been reported along with a second ABCA4 variant in several individuals with Stargardt disease (see for examples Zernant et al. 2018. PubMed ID: 29848554; Nassisi et al. 2019. PubMed ID: 31614660; Weisschuh et al. 2020. PubMed ID: 32531858; Song et al. 2021. PubMed ID: 34440443). This variant has also been reported as a 'third' ABCA4 variant along with two likely pathogenic ABCA4 variants (Fujinami et al. 2019. PubMed ID: 29925512). This variant is relatively common, being reported in 1.2% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and with a global allele frequency of 0.47% including 5 homozygotes (http://gnomad.broadinstitute.org/variant/1-94496509-C-T). Even though common, it has been reported that this variant is significantly enriched in patients compared to the general population (Zernant et al. 2018. PubMed ID: 29848554). A functional study using a mini-gene splicing assay found that this deep intronic variant causes skipping of exon 28, but only in a small proportion of the mRNA (Sangermano et al. 2019. PubMed ID: 30643219 ). A cohort analysis of individuals with this variant found that the median age of onset for Stargardt disease was 52 years of age which is considered late-onset and penetrance was estimated at ~40% (Runhart. 2019. PubMed ID: 31618761). Given all the evidence, we interpret c.4253+43G>A as likely pathogenic, but with a mild and late-onset phenotype that is likely only observed when in trans with a more severe pathogenic variant.
Invitae	RCV000085618	SCV004509390	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 28 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. This variant is present in population databases (rs61754045, gnomAD 1.3%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with Stargardt disease, generally with later onset and possibly reduced penetrance (PMID: 29848554, 31618761). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99265). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic.
Retina International	RCV000085618	SCV000117757	not provided	not provided		no assertion provided	not provided
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV001290208	SCV001478092	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-26	no assertion criteria provided	clinical testing	c.4253+43G>A has been found to be associated with autosomal recessive Stargardt disease (STGD1). Its presence explained 6-14% of monoallelic ABCA4 carriers in three separate STGD1 cohorts and was significantly enriched in monoallelic ABCA4 carriers (OR=12.87). Penetrance was estimated to be ~40% and the variant was described as an “hypomorph”. Its effect was proven experimentally, showing that the variant results in partial exon skipping through the disruption of putative splice silencers. The phenotype described is milder than classical Stargardt disease with late-onset and foveal sparing.