Submissions for variant NM_000350.3(ABCA4):c.32T>C (p.Leu11Pro)

gnomAD frequency: 0.00001  dbSNP: rs62645946

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779010	SCV000915451	pathogenic	ABCA4-related disorder	2018-12-04	criteria provided, single submitter	clinical testing	The ABCA4 c.32T>C (p.Leu11Pro) missense variant has been reported in at least six studies in which it is found in a total of eight individuals, including in a compound heterozygous state in six subjects diagnosed with Stargardt disease (STGD), and in a heterozygous state in one individual with STGD and one with late onset fundus flavimaculatus (Rozet et al. 1998; Valverde et al. 2007; Maia-Lopes et al. 2009; Riveiro-Alvarez et al. 2013; Salles et al. 2018). The p.Leu11Pro variant was absent from 110 healthy controls and is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele so the variant is presumed to be rare. Based on the evidence the p.Leu11Pro 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.
Blueprint Genetics	RCV001074134	SCV001239703	pathogenic	Retinal dystrophy	2019-01-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085568	SCV001587237	pathogenic	not provided	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 11 of the ABCA4 protein (p.Leu11Pro). This variant is present in population databases (rs62645946, gnomAD 0.0009%). This missense change has been observed in individual(s) with ABCA4-related conditions (PMID: 17325136, 19365591, 29925512, 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: 99217). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723665	SCV001950201	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Leu11Pro variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3-S. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
3billion, Medical Genetics	RCV002051808	SCV002318729	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099217, PMID:9781034). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 19365591). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 17325136). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.948>=0.6, 3CNET: 0.972>=0.75). A missense variant is a common mechanism associated with Stargardt disease 1. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
AiLife Diagnostics, AiLife Diagnostics	RCV000085568	SCV002501243	likely pathogenic	not provided	2021-06-15	criteria provided, single submitter	clinical testing
Mendelics	RCV002247489	SCV002517492	pathogenic	Age related macular degeneration 2	2022-05-04	criteria provided, single submitter	clinical testing
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324510	SCV004030387	pathogenic	Stargardt disease	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324509	SCV004030398	pathogenic	Cone-rod dystrophy	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Fulgent Genetics, Fulgent Genetics	RCV005025156	SCV005662732	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-01-30	criteria provided, single submitter	clinical testing
Retina International	RCV000085568	SCV000117705	not provided	not provided		no assertion provided	not provided