Submissions for variant NM_000350.3(ABCA4):c.4457C>T (p.Pro1486Leu)

gnomAD frequency: 0.00009  dbSNP: rs61750145

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408536	SCV000281890	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085636	SCV000511897	pathogenic	not provided	2022-09-22	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: 11328725, 21911583, 30093795, 23143460, 11527935, 17932850, 9973280, 18285826, 28118664, 25412400, 22247458, 28559085, 31129250, 31456290, 32845050, 32036094)
Mendelics	RCV000408536	SCV001135340	pathogenic	Severe early-childhood-onset retinal dystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085636	SCV001205168	pathogenic	not provided	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1486 of the ABCA4 protein (p.Pro1486Leu). This variant is present in population databases (rs61750145, gnomAD 0.07%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 18285826, 22247458, 23755871, 28559085, 30093795). 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: 99283). 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	RCV001074852	SCV001240453	pathogenic	Retinal dystrophy	2019-07-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085636	SCV001248245	pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198562	SCV001369551	pathogenic	Age related macular degeneration 2	2019-12-02	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP2,PM3,PS1.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085636	SCV001448014	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000408536	SCV001521356	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2020-08-01	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV002498456	SCV002811043	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2022-01-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074852	SCV005068651	likely pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Retina International	RCV000085636	SCV000117775	not provided	not provided		no assertion provided	not provided
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002829	SCV001160846	pathogenic	Stargardt disease	2019-06-23	no assertion criteria provided	research
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV000408536	SCV005047017	pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732671	SCV005351073	pathogenic	ABCA4-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The ABCA4 c.4457C>T variant is predicted to result in the amino acid substitution p.Pro1486Leu. This variant has been reported many times in the homozygous and compound heterozygous state in individuals with ABCA4-related retinal disease (see for examples: Table S1, Stone et al. 2017. PubMed ID: 28559085; Del Pozo-Valero et al. 2020. PubMed ID: 31129250; Table S4, Rodríguez-Muñoz et al. 2020. PubMed ID: 32036094; Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.062% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.