Submissions for variant NM_000350.3(ABCA4):c.3481C>T (p.Arg1161Cys)

gnomAD frequency: 0.00001  dbSNP: rs553776104

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523804	SCV000621534	uncertain significance	not provided	2019-08-07	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29925512)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000523804	SCV001418914	likely pathogenic	not provided	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1161 of the ABCA4 protein (p.Arg1161Cys). This variant is present in population databases (rs553776104, gnomAD 0.01%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 29925512). ClinVar contains an entry for this variant (Variation ID: 452706). 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.Arg1161 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26780318, 29925512, 31814694). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005407681	SCV006072616	likely pathogenic	Retinitis pigmentosa	2025-04-08	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.3481C>T (p.Arg1161Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251460 control chromosomes. c.3481C>T has been reported in the literature in individuals affected with Retinitis Pigmentosa (Lin_2024, Fujinam_2019). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.3482G>A, p.Arg1161His), supporting the critical relevance of codon 1161 to ABCA4 protein function. 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: 29925512, 38219857). ClinVar contains an entry for this variant (Variation ID: 452706). Based on the evidence outlined above, the variant was classified as likely pathogenic.