Submissions for variant NM_000350.3(ABCA4):c.1957C>T (p.Arg653Cys) (rs61749420)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg	RCV000408546	SCV000281839	likely pathogenic	Stargardt disease 1	2016-01-01	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000085452	SCV000574771	pathogenic	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000763047	SCV000893528	likely pathogenic	Cone-rod dystrophy 3; Age-related macular degeneration 2; Stargardt disease 1; Retinitis pigmentosa 19	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000085452	SCV001202188	pathogenic	not provided	2020-09-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 653 of the ABCA4 protein (p.Arg653Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs61749420, ExAC 0.002%). This variant has been observed in several individuals affected with Stargardt disease, and was observed to segregate with cone rod dystrophy in a family (PMID: 28559085, 23776498). ClinVar contains an entry for this variant (Variation ID: 99108). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg653 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9466990, 10413692, 19074458). 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	RCV001074668	SCV001240260	pathogenic	Retinal dystrophy	2019-03-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085452	SCV001446861	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV000408546	SCV001548139	likely pathogenic	Stargardt disease 1	2021-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000085452	SCV001782833	pathogenic	not provided	2021-08-11	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33375396, 10958763, 33301772, 28559085, 23776498, 29925512, 32619608, 30204727, 23982839, 18652558, 25444351, 25097154, 23953153, 19265867, 15192030, 28355279, 27939946, 23499370, 11702214, 26957898, 26992781)
Retina International	RCV000085452	SCV000117589	not provided	not provided		no assertion provided	not provided
Human Genetics - Radboudumc,Radboudumc	RCV000085452	SCV001957874	likely pathogenic	not provided		no assertion criteria provided	clinical testing