Submissions for variant NM_000350.3(ABCA4):c.2971G>C (p.Gly991Arg)

gnomAD frequency: 0.00194  dbSNP: rs61749455

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085531	SCV001117607	pathogenic	not provided	2025-01-21	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 991 of the ABCA4 protein (p.Gly991Arg). This variant is present in population databases (rs61749455, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Stargardt disease, often with later onset than typical Stargardt (PMID: 11379881, 25066811, 28446513, 32278709; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99182). 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%. This variant disrupts the p.Gly991 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23982839, 32036094; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001073380	SCV001238921	pathogenic	Retinal dystrophy	2019-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000085531	SCV001768161	pathogenic	not provided	2024-11-07	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: 22328824, 23982839, 25082829, 14517951, 35120629, 32307445, 25283059, 11379881, 23953153, 18024811, 29178665, 28041643, 29925512, 32581362, 32278709, 32619608, Cornelis2023[paper], 34954332, 28005406, 24743636, 37126335, 35089312, 15017103, 35260635)
Mendelics	RCV002247488	SCV002516200	likely pathogenic	Age related macular degeneration 2	2022-05-04	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989317	SCV004807785	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2024-03-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815096	SCV005070762	likely pathogenic	Optic atrophy	2023-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001073380	SCV005073487	likely pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV004699118	SCV005201044	pathogenic	Retinitis pigmentosa 19	2024-08-15	criteria provided, single submitter	clinical testing	Combined evidence strength is Very Strong: ClinVar classifies this variant as Pathogenic, 2 stars (PP5). Equivalent variant chr1:94044692 C>T (Gly991Arg) is classified Pathogenic, 1 star, by ClinVar (PS1). Hot-spot of length 17 amino-acids has 16 missense/in-frame variants (10 pathogenic variants, 6 uncertain variants and no benign), which qualifies as moderate pathogenic.UniProt protein ABCA4_HUMAN has 305 missense/in-frame variants (217 pathogenic variants, 88 uncertain variants and no benign), which qualifies as moderate pathogenic (PM1). Alternative variant chr1:94044691 C>A (Gly991Val) is classified Likely Pathogenic by LOVD (PM5).GnomAD genomes homozygous allele count = 1. GnomAD exomes homozygous allele count = 1 (PM2). MetaRNN = 0.105 is between 0.00692 and 0.108 = strong benign. Reducing to strength supporting in view of the clinical evidence reported in PP5_Very Strong (BP4).We identified this compound heterozygous variant in a 36-year-old woman diagnosed with retinitis pigmentosa. Her parents are not consanguineous.
CeGaT Center for Human Genetics Tuebingen	RCV000085531	SCV005433182	likely pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Strong, PM5, PM2:Supporting
Fulgent Genetics, Fulgent Genetics	RCV005025152	SCV005659444	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-01-05	criteria provided, single submitter	clinical testing
Retina International	RCV000085531	SCV000117668	not provided	not provided		no assertion provided	not provided
Eurofins Ntd Llc (ga)	RCV000085531	SCV000340465	uncertain significance	not provided	2016-03-17	flagged submission	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505091	SCV000598957	likely pathogenic	Macular dystrophy	2015-01-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004529886	SCV004724085	likely pathogenic	ABCA4-related disorder	2024-09-06	no assertion criteria provided	clinical testing	The ABCA4 c.2971G>C variant is predicted to result in the amino acid substitution p.Gly991Arg. This variant has been reported along with a second ABCA4 variant in individuals with Stargardt disease (see for examples Jaakson et al. 2003. PubMed ID: 14517951; Sisk et al. 2014. PubMed ID: 24743636; Duncker et al. 2014. PubMed ID: 25283059; Table S2 in Carss et al. 2016. PubMed ID: 28041643; Table S1 in Fujinami et al. 2018. PubMed ID: 29925512; Del Pozo-Valero et al. 2020. PubMed ID: 32619608). Note that several of these publications list the third variant c.3899G>A (p.Arg1300Gln) which we classify as benign and is likely to be in cis with this variant. This variant is reported in 0.73% of alleles in individuals of African descent in gnomAD, indicating this variant is relatively common. Given the evidence, we interpret this variant as likely pathogenic.