Submissions for variant NM_000350.3(ABCA4):c.3413T>A (p.Leu1138His)

dbSNP: rs1287053724

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268101	SCV001446755	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814048	SCV005073243	likely pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001268101	SCV005831381	pathogenic	not provided	2024-08-07	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 1138 of the ABCA4 protein (p.Leu1138His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Stargardt disease (PMID: 29848554). 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: 986929). 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%. This variant disrupts the p.Leu1138 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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.