Submissions for variant NM_000350.3(ABCA4):c.4328G>A (p.Arg1443His)

gnomAD frequency: 0.00003  dbSNP: rs61750142

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408447	SCV000281886	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779005	SCV000915446	pathogenic	ABCA4-Related Disorders	2019-01-12	criteria provided, single submitter	clinical testing	Across a selection of the literature, the ABCA4 c.4328G>A (p.Arg1443His) missense variant has been reported in a compound heterozygous state in at least five individuals, including four affected with Stargardt disease, one described as affected with ABCA4-associated disease and one with ABCA4-associated retinopathies (Rivera et al. 2000; Testa et al. 2012; Chacón-Camacho et al. 2013; Fujinami et al. 2013; Nõupuu et al. 2014; Schulz et al. 2017). In addition Roberts et al. (2011) identified the p.Arg1443His variant in one patient allele from a cohort of 181 individuals with ABCA4-associated retinopathies. The variant was absent from 220 control individuals and is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Arg1443 residue is noted to be well conserved. Biswas-Fiss et al. (2010) compared the ABCA4 wild type structure with that of three variant structures, including the p.Arg1443His variant using CD spectral analysis. The p.Arg1443His variant structure was shown to be significantly altered with loss of alpha-helical secondary structure. The same study also demonstrated decreased binding affinity to its substrate. Based on the collective evidence, the p.Arg1443His variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics	RCV001073587	SCV001239138	pathogenic	Retinal dystrophy	2019-07-06	criteria provided, single submitter	clinical testing
Invitae	RCV000085631	SCV001418752	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1443 of the ABCA4 protein (p.Arg1443His). This variant is present in population databases (rs61750142, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive Stargardt disease (PMID: 15161829, 22661472, 23419329, 23982839, 28118664, 29925512). 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: 99278). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 20404325). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Molecular Genetics, University of Zurich	RCV000408447	SCV001548105	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
3billion	RCV000408447	SCV002058940	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099278, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000021, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.805, 3CNET: 0.958, PP3_P). A missense variant is a common mechanism associated with Stargardt disease 1 (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Mendelics	RCV002247490	SCV002517484	pathogenic	Age related macular degeneration 2	2022-05-04	criteria provided, single submitter	clinical testing
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324511	SCV004030420	pathogenic	Stargardt disease	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
PreventionGenetics, part of Exact Sciences	RCV003407476	SCV004106330	likely pathogenic	ABCA4-related condition	2023-07-22	criteria provided, single submitter	clinical testing	The ABCA4 c.4328G>A variant is predicted to result in the amino acid substitution p.Arg1443His. This variant was reported in the compound heterozygous state in several individuals with autosomal recessive ABCA4-related disorders (Rivera et al 2000. PubMed ID: 10958763; Fujinami K et al 2018. PubMed ID: 29925512; Salles MV et al 2018. PubMed ID: 30093795; Fujinami K et al 2013. PubMed ID: 23982839; Testa F et al 2012. PubMed ID: 22661472; Nõupuu K et al 2014. PubMed ID: 25301883; ). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94496008-C-T). This variant is interpreted as likely pathogenic.
Dept Of Ophthalmology, Nagoya University	RCV001073587	SCV004707412	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Retina International	RCV000085631	SCV000117770	not provided	not provided		no assertion provided	not provided