Submissions for variant NM_000350.3(ABCA4):c.4519G>A (p.Gly1507Arg)

gnomAD frequency: 0.00005  dbSNP: rs568792949

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408586	SCV000281894	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074181	SCV001239751	pathogenic	Retinal dystrophy	2019-02-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380976	SCV001579216	pathogenic	not provided	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1507 of the ABCA4 protein (p.Gly1507Arg). This variant is present in population databases (rs568792949, gnomAD 0.1%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 23499370, 26593885, 27030965, 28041643). 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: 236115). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401161	SCV004122366	likely pathogenic	Stargardt disease	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.4519G>A (p.Gly1507Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 172758 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Stargardt Disease (0.00016 vs 0.0014), allowing no conclusion about variant significance. c.4519G>A has been reported in the literature as a biallelic compound heterozygous genotype in individuals affected with Stargardt Disease (example, Fujinami_2013, Huckfeldt_2016, Lambertus_2016, Klufas_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28041643, 23499370, 27030965, 32307445, 28248825, 27699414, 26593885). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074181	SCV005073145	likely pathogenic	Retinal dystrophy	2017-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031808	SCV005658889	likely pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-04-01	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000408586	SCV000598976	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research
Dept Of Ophthalmology, Nagoya University	RCV001074181	SCV004707357	uncertain significance	Retinal dystrophy	2023-10-01	flagged submission	research
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV000408586	SCV005047018	pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732801	SCV005361342	pathogenic	ABCA4-related disorder	2024-09-04	no assertion criteria provided	clinical testing	The ABCA4 c.4519G>A variant is predicted to result in the amino acid substitution p.Gly1507Arg. This variant has been reported in the compound heterozygous state in multiple individuals with ABCA4-related retinal disease (see for examples: Fujinami et al. 2013. PubMed ID: 23499370; Table S1, Ścieżyńska et al 2015. PubMed ID: 26593885; Table S1, Del Pozo-Valero et al. 2020. PubMed ID: 32619608; Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.10% of alleles in individuals of Latino descent in gnomAD. Given the evidence, we interpret this variant as pathogenic.