Submissions for variant NM_000350.3(ABCA4):c.3064G>A (p.Glu1022Lys)

gnomAD frequency: 0.00001  dbSNP: rs61749459

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408496	SCV000281858	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085545	SCV000511889	likely pathogenic	not provided	2016-10-12	criteria provided, single submitter	clinical testing	The E1022K variant has been published in association with ABCA4-related disorders (Webster et al., 2001; Stone et al., 2003; Stenirri et al., 2004; Fumagalli et al., 2001; Fujinami et al., 2013; Fujinami et al., 2015). The E1022K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E1022K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (T1019A, T1019M, F1026L) have been reported in the Human Gene Mutation Database in association with Stargardt disease (Stenson et al., 2014). Therefore, based on the currently available information, E1022K is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085545	SCV001218586	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs61749459, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1022 of the ABCA4 protein (p.Glu1022Lys). This missense change has been observed in individuals with Stargardt disease (PMID: 11702214, 23982839, 30834176). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 99196).
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324507	SCV004030365	pathogenic	Stargardt disease	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
PreventionGenetics, part of Exact Sciences	RCV004529887	SCV004106587	likely pathogenic	ABCA4-related disorder	2023-10-06	criteria provided, single submitter	clinical testing	The ABCA4 c.3064G>A variant is predicted to result in the amino acid substitution p.Glu1022Lys. This variant has been reported many times in individuals with Stargardt disease (see for examples Fumagalli et al. 2001. PubMed ID: 11702214; Table S1 in Fujinami et al. 2019. PubMed ID: 29925512; Table S4 in Panneman et al. 2023. PubMed ID: 36819107). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94509018-C-T). Given the evidence, we interpret this variant as likely pathogenic.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815097	SCV005068412	likely pathogenic	Retinal dystrophy	2020-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800282	SCV005422565	pathogenic	Retinitis pigmentosa	2024-10-22	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.3064G>A (p.Glu1022Lys) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251268 control chromosomes. c.3064G>A has been reported in the literature in multiple compound heterozygous or homozygous individuals affected with Retinitis Pigmentosa or Stargardt Disease (e.g. Yohe_2020, Downes_2012, Panneman_2023). These data indicate that the variant is very 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: 23143460, 36819107, 31816670). ClinVar contains an entry for this variant (Variation ID: 99196). Based on the evidence outlined above, the variant was classified as pathogenic.
Retina International	RCV000085545	SCV000117682	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000408496	SCV000598958	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research