Submissions for variant NM_000350.3(ABCA4):c.4462T>C (p.Cys1488Arg)

gnomAD frequency: 0.00001  dbSNP: rs61750146

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408472	SCV000281892	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085637	SCV000321351	pathogenic	not provided	2016-10-12	criteria provided, single submitter	clinical testing	The C1488R pathogenic variant in the ABCA4 gene has been published previously in association with Stargardt disease (Lewis et al., 1999; Briggs et al., 2001; Webster et al., 2001). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. C1488R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies have shown that C1488R results in lowered ATPase activity compared to wild type (Sun et al., 2000). Missense variants in the same codon (C1488Y/F) and in nearby residues (P1486L, C1490Y) have been reported in the Human Gene Mutation Database in association with Stargardt disease (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Fulgent Genetics, Fulgent Genetics	RCV000763043	SCV000893524	likely pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000085637	SCV001222273	pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1488 of the ABCA4 protein (p.Cys1488Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with ABCA4-related conditions (PMID: 22449572, 28559085, 29555955, 29925512). 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: 99284). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001073630	SCV001239181	pathogenic	Retinal dystrophy	2019-07-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085637	SCV001248244	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Very Strong, PM1, PM2, PM5, PP3, PS3:Supporting
Institute of Medical Molecular Genetics, University of Zurich	RCV000408472	SCV001548141	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085637	SCV001905554	likely pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
3billion	RCV001808325	SCV002058249	pathogenic	Retinitis pigmentosa 19	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099284, PMID:9973280, PS1_S). Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099285,VCV000099286, PMID:10958763,11328725, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93, 3CNET: 0.99, PP3_P). A missense variant is a common mechanism associated with Retinitis pigmentosa 19 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000011, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000408472	SCV002581284	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-02-15	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001073630	SCV004707379	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Retina International	RCV000085637	SCV000117776	not provided	not provided		no assertion provided	not provided