Submissions for variant NM_000350.3(ABCA4):c.4463G>T (p.Cys1488Phe)

gnomAD frequency: 0.00001  dbSNP: rs61750147

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085639	SCV001224356	pathogenic	not provided	2024-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 1488 of the ABCA4 protein (p.Cys1488Phe). This variant is present in population databases (rs61750147, gnomAD 0.002%). This missense change has been observed in individuals with Stargardt disease (PMID: 20647261; internal data). ClinVar contains an entry for this variant (Variation ID: 99286). 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%. This variant disrupts the p.Cys1488 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22449572, 28559085, 29555955, 29925512). 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.
Molecular Genetics, Royal Melbourne Hospital	RCV002225081	SCV002503668	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace cysteine with phenylalanine at codon 1488 of the ABCA4 protein, p.(Cys1488Phe). The cysteine residue is highly conserved (100 vertebrates, UCSC), and is predicted to form a disulphide bond. There is a large physicochemical difference between cysteine and phenylalanine. The variant is present in a large population cohort at a frequency of 0.0008%, which is consistent with recessive disease (rs61750147, 2/243,254 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in at least one Stargardt disease case with another pathogenic variant (PMID: 11673412). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Two different missense changes at the same position (p.Cys1488Tyr, p.Cys1488Arg) determined to be likely pathogenic/pathogenic have been seen before (ClinVar IDs: 99284, 99285). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PM5, PM3_Supporting, PP3.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002225081	SCV002767513	pathogenic	Severe early-childhood-onset retinal dystrophy	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease (MIM #248200), cone-rod dystrophy 3 (MIM #6041163), fundus flavimaculatus (MIM #248200), early-onset severe Retinal dystrophy (MIM #248200) and retinitis pigmentosa 19 (MIM #601718). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (29 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (highest allele count: 15 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located at an annotated cysteine residue that is involved in a disulphide bond (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case has very strong previous evidence for pathogenicity. p.(Cys1488Arg) and p.(Cys1488Tyr) have been identified in multiple individuals with Stargardt disease (ClinVar; PMID: 22449572, 23769331, 29854428, 31766579, 30820146). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in at least five individuals with Stargardt disease (Clinvar; PMID: 11328725). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005025158	SCV005659780	likely pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-02-22	criteria provided, single submitter	clinical testing
Retina International	RCV000085639	SCV000117778	not provided	not provided		no assertion provided	not provided