Submissions for variant NM_000350.3(ABCA4):c.658C>T (p.Arg220Cys)

gnomAD frequency: 0.00001  dbSNP: rs61748538

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085832	SCV001417294	pathogenic	not provided	2024-12-07	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 220 of the ABCA4 protein (p.Arg220Cys). This variant is present in population databases (rs61748538, gnomAD 0.007%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 29854428, 29925512, 30093795). ClinVar contains an entry for this variant (Variation ID: 99471). 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%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000085832	SCV001961126	likely pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470767	SCV002767272	pathogenic	Severe early-childhood-onset retinal dystrophy	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, 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 ABCA4-related disorders, including Stargardt disease 1 (MIM#248200). (I) 0106 - This gene is associated with autosomal recessive disease. However, pseudo-dominant inheritance has been suggested (PMID: 26527198). (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 arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (6 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in homozygote and compound heterozygote individuals with Stargardt disease (PMIDs: 19074458, 23953153, 25066811, 28041643, 29854428, 30093795), and in individuals with unstated zygosity (ClinVar; PMIDs: 24154662, 11328725). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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	RCV002498460	SCV002805621	likely pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2021-08-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000504919	SCV005070603	likely pathogenic	Retinal dystrophy	2017-01-01	criteria provided, single submitter	clinical testing
Retina International	RCV000085832	SCV000117975	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504919	SCV000599019	likely pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research