Submissions for variant NM_000350.3(ABCA4):c.4139C>T (p.Pro1380Leu)

gnomAD frequency: 0.00023  dbSNP: rs61750130

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078666	SCV000110525	pathogenic	not provided	2013-08-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000078666	SCV000329047	pathogenic	not provided	2023-06-12	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: 26766544, 28559085, 29925512, 31429209, 32531858, 33706644, 34315337, 35456422, 33369172, 32037395, 25283059, 15579991, 9973280, 25087612, 11527935, 28341476, 28041643, 19074458, 10396622, 16682602, 30634128, 30204727, 30718709, 11017087, 32467599, 31456290, 32581362, 33375396, 34426522, 31573552, 31589614, 32619608, 27030965, 28947085, 35119454)
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000454310	SCV000538009	pathogenic	Mandibulofacial dysostosis with mental deficiency	2015-07-24	criteria provided, single submitter	clinical testing	This variant has been observed, either as homozygous (Hwang JC et al., 2009) or compound heterozygous (Lewis RA et al., 1999) in individuals who have been diagnosed with Stargardt disease. It co-segregates with disease and was found in trans with the known pathogenic variant, G1961E (Duncker T et al., 2015). In the protein, it is present in the helical transmembrane domain 7 and is close to the nucleotide binding domain-1. Studies in HEK 293 cells showed that, compared with wild-type, the protein yield and ATP-binding capacity of this variant was reduced (Sun H et al., 2000). Finally, multiple computational algorithms predict this variant to be deleterious and its frequency in the population databases (1000 Genomes, Exome Sequencing Project [ESP] and ExAC) is either absent or very low. Therefore, this variant meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing.
Fulgent Genetics, Fulgent Genetics	RCV000763044	SCV000893525	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2021-10-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778258	SCV000914430	pathogenic	ABCA4-Related Disorders	2018-08-21	criteria provided, single submitter	clinical testing	The ABCA4 c.4139C>T (p.Pro1380Leu) missense variant has been reported in at least ten studies in which it is found in at least 38 individuals with either Stargardt disease (STGD), cone-rod dystrophy or age related macular degeneration including in five individuals in a homozygous state, at least 29 in a compound heterozygous state, and four individuals in a heterozygou state (Shroyer et al. 1999; Lewis et al. 1999; Shroyer et al. 2001; Briggs et al. 2001; Oh et al. 2004; Fingert et al. 2006; Hwang et al. 2009; Cideciyan et al. 2009; Chacón-Camacho et al. 2013; Duncker et al. 2015). The p.Pro1380Leu variant has been shown to segregate with STGD disease in at least three families (Lewis et al. 1999; Shroyer et al. 2001; Cideciyan et al. 2009). The variant has not been reported in association with retinitis pigmentosa. The p.Pro1380Leu variant was absent from at least 895 controls and is reported at a frequency of 0.001973 in the Ashkenazi Jewish population of the Genome Aggregation Database. In vitro analysis in HEK-293 cells demonstrated that the p.Pro1380Leu variant resulted in reduced expression of the protein and defective ATP binding (Sun et al. 2000). Based on the collective evidence, the p.Pro1380Leu variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000078666	SCV001211297	pathogenic	not provided	2024-01-31	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 1380 of the ABCA4 protein (p.Pro1380Leu). This variant is present in population databases (rs61750130, gnomAD 0.2%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 9973280, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7904). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075868	SCV001241509	pathogenic	Retinal dystrophy	2019-08-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000078666	SCV001249460	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000078666	SCV001447241	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV000008362	SCV001548095	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000078666	SCV002020375	pathogenic	not provided	2021-06-23	criteria provided, single submitter	clinical testing
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV000787498	SCV004030409	pathogenic	Stargardt disease	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
OMIM	RCV000008362	SCV000028570	pathogenic	Severe early-childhood-onset retinal dystrophy	2006-05-01	no assertion criteria provided	literature only
OMIM	RCV000023139	SCV000044430	risk factor	MACULAR DEGENERATION, AGE-RELATED, 2, SUSCEPTIBILITY TO	2006-05-01	no assertion criteria provided	literature only
Retina International	RCV000078666	SCV000117745	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000008362	SCV000598970	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787498	SCV000926464	likely pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000787498	SCV001160848	pathogenic	Stargardt disease	2019-06-23	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000078666	SCV001922450	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078666	SCV001951354	pathogenic	not provided		no assertion criteria provided	clinical testing