Submissions for variant NM_000350.3(ABCA4):c.4978C>T (p.Pro1660Ser)

gnomAD frequency: 0.00001  dbSNP: rs1211325812

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Molecular Genetics, University of Zurich	RCV001353015	SCV001548117	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379165	SCV001576915	pathogenic	not provided	2024-06-21	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1660 of the ABCA4 protein (p.Pro1660Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with inherited retinal dystrophy (PMID: 22247458; Invitae). ClinVar contains an entry for this variant (Variation ID: 1048159). 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.Pro1660 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 28118664), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001724300	SCV001950199	uncertain significance	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Pro1660Ser 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. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001724300	SCV005381441	likely pathogenic	Retinitis pigmentosa	2024-08-05	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.4978C>T (p.Pro1660Ser) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of 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 8e-06 in 251454 control chromosomes. c.4978C>T has been reported in the literature in individuals affected with Retinitis Pigmentosa/ inherited retinal dystrophy (Cideciyan_2012, Pfau_2022, Lin_2022, Weisschuh_J2024). These data indicate that the variant is likely to be associated with disease. 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: 22247458, 38219857, 35076026, 37734845). ClinVar contains an entry for this variant (Variation ID: 1048159). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV001353015	SCV005047042	pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004733268	SCV005360095	pathogenic	ABCA4-related disorder	2024-08-22	no assertion criteria provided	clinical testing	The ABCA4 c.4978C>T variant is predicted to result in the amino acid substitution p.Pro1660Ser. This variant has been reported along with a second ABCA4 variant in several individuals with inherited retinal disease (Cideciyan et al. 2012. PubMed ID: 22247458; Table S2, Schulz et al. 2017. PubMed ID: 28118664; Table S2, Zampaglione et al. 2020. PubMed ID: 32037395; Table S1, Weisschuh et al. 2024. PubMed ID: 37734845). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret this variant as pathogenic.