Submissions for variant NM_000350.3(ABCA4):c.4594G>A (p.Asp1532Asn)

gnomAD frequency: 0.00006  dbSNP: rs62642574

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000085657	SCV000229391	pathogenic	not provided	2015-02-24	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000177510	SCV000281897	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085657	SCV001201993	pathogenic	not provided	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1532 of the ABCA4 protein (p.Asp1532Asn). This variant is present in population databases (rs62642574, gnomAD 0.2%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 9973280, 11726554, 19217903, 22589445, 24409374, 29925512; internal data). 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: 99304). 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.
Blueprint Genetics	RCV001074286	SCV001239859	pathogenic	Retinal dystrophy	2019-05-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000085657	SCV001769717	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28118664, 37705246, 37869022, 37930186, 9973280, 19217903, 22589445, 30055151, 29925512, 28559085, 29343940, 32013026, 31456290, 31589614, 32037395, 24409374, 33505770, 11726554)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235039	SCV003934465	pathogenic	Retinitis pigmentosa	2023-05-30	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.4594G>A (p.Asp1532Asn) results in a conservative amino acid change in 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 0.00011 in 251478 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.00011 vs 0.0014), allowing no conclusion about variant significance. c.4594G>A has been reported in the literature in multiple individuals affected with Stargardt disease and bull's eye maculopathy (examples: Lewis_1999, Shroyer_2001, Cella_2009, Giani_2012, Verdina_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11726554, 19217903 , 22589445, 24409374 , 9973280 ). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000177510	SCV004032319	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2023-08-01	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM2_SUP,PP3
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074286	SCV005071043	likely pathogenic	Retinal dystrophy	2019-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000177510	SCV005399007	pathogenic	Severe early-childhood-onset retinal dystrophy	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200) and other inherited retinal diseases (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (29 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Asp1532Tyr) has been reported in a compound heterozygous individual with late-onset Stargardt disease (PMID: 23953153). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic six times and likely-pathogenic twice (ClinVar). This variant has been reported in multiple compound heterozygous individuals with Stargardt disease, autosomal recessive ABCA4-related retinopathy and late-onset maculopathy (PMIDs: 32013026, 9973280, 19217903, 23953153, 33505770, 29343940). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005025161	SCV005658872	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-01-03	criteria provided, single submitter	clinical testing
Retina International	RCV000085657	SCV000117797	not provided	not provided		no assertion provided	not provided
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002826	SCV001160843	likely pathogenic	maculopathy	2019-06-23	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV001535669	SCV001749732	not provided	Cone-rod dystrophy 3; Retinitis pigmentosa 19; Age-related macular degeneration		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 02-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004529890	SCV004118321	pathogenic	ABCA4-related disorder	2024-09-09	no assertion criteria provided	clinical testing	The ABCA4 c.4594G>A variant is predicted to result in the amino acid substitution p.Asp1532Asn. This variant has been reported to be causative for autosomal recessive Stargardt disease (see for examples: Lewis et al. 1999. PubMed ID: 9973280; Table S2, Zampaglione et al. 2020. PubMed ID: 32037395; Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.21% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.