Submissions for variant NM_000350.3(ABCA4):c.4540-8T>C

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003823631	SCV004622720	likely benign	not provided	2023-08-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005063178	SCV005726008	uncertain significance	not specified	2024-11-22	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.4540-8T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4540-8T>C has been reported in the literature in cis with a pathogenic variant on one allele which was in trans with a pathogenic 2nd allele in at least 1 individual affected with Stargardt disease (example, Del Pozo_2020, Khan_2020). These report(s) do not provide unequivocal conclusions about association of the variant with ABCA4-related conditions. Co-occurrences with other pathogenic variant(s) have been reported (ABCA4 c.5882G>A, p.Gly1961Glu), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32619608, 32307445). ClinVar contains an entry for this variant (Variation ID: 2965465). Based on the evidence outlined above, the variant was classified as uncertain significance.