Submissions for variant NM_000350.3(ABCA4):c.5113C>T (p.Arg1705Trp)

gnomAD frequency: 0.00001  dbSNP: rs771038310

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779001	SCV000915442	uncertain significance	ABCA4-related disorder	2017-09-10	criteria provided, single submitter	clinical testing	The ABCA4 c.5113C>T (p.Arg1705Trp) missense variant has been reported in at least three studies in which it is found in at least two patients in a compound heterozygous state, one of whom was diagnosed with Stargardt disease before age ten and one diagnosed with a retinopathy noted to be consistent with ABCA4-related retinal disease (Ernest et al. 2009; Fujinami et al. 2013; Lambertus et al. 2015). The p.Arg1705Trp variant was absent from 100 controls and is reported at a frequency of 0.00007 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg1705Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV000994038	SCV001147330	uncertain significance	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV001199620	SCV001162384	pathogenic	Cone-rod dystrophy	2020-01-09	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000994038	SCV001213376	pathogenic	not provided	2024-11-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1705 of the ABCA4 protein (p.Arg1705Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Stargardt disease (PMID: 25444351, 32307445; internal data). ClinVar contains an entry for this variant (Variation ID: 632119). 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.Arg1705 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17325179, 23419329, 23769331). 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	RCV001074860	SCV001240462	likely pathogenic	Retinal dystrophy	2019-07-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV002267624	SCV002549831	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2022-06-21	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM3, PM2_SUP, PM5_SUP, PP3, PP4
Institute of Human Genetics, University of Leipzig Medical Center	RCV003322616	SCV004027673	likely pathogenic	Retinitis pigmentosa 1	2023-07-04	criteria provided, single submitter	clinical testing	Criteria applied: PM1,PM5,PM2_SUP,PP3,PP4, PS4_MOD
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074860	SCV005072180	likely pathogenic	Retinal dystrophy	2013-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760780	SCV005368128	likely pathogenic	Retinitis pigmentosa 19	2024-06-19	criteria provided, single submitter	clinical testing	Criteria applied: PM2,PM3,PM5,PP3
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV002267624	SCV005047044	pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV000779001	SCV005361178	pathogenic	ABCA4-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The ABCA4 c.5113C>T variant is predicted to result in the amino acid substitution p.Arg1705Trp. This variant has been reported along with a second ABCA4 variant in individuals with ABCA4-related retinal disease (Fujinami et al. 2013. PubMed ID: 23982839; Lambertus et al. 2014. PubMed ID: 25444351; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858;Table S1, Lin et al. 2024. PubMed ID: 38219857). Alternate substitutions of this amino acid residue (p.Arg1705Leu and p.Arg1705Gln) have also been reported in individuals with ABCA4-related retinal disease (Table S1, Fujinami et al. 2018. PubMed ID: 29925512). This variant is reported in 0.0040% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.