Submissions for variant NM_000350.3(ABCA4):c.4222T>C (p.Trp1408Arg)

gnomAD frequency: 0.00001  dbSNP: rs61750135

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000210333	SCV000281881	likely pathogenic	Retinal dystrophy	2012-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085613	SCV000321350	pathogenic	not provided	2018-10-04	criteria provided, single submitter	clinical testing	The W1408R pathogenic variant in the ABCA4 gene has been reported previously in autosomal recessive Stargardt disease in affected individuals when in trans with another pathogenic variant (Lewis et al., 1999). The W1408R variant has been reported on the same allele (in cis) with the R1640W variant in families with Stargardt disease, and in a family presenting with both Stargardt disease and retinitis pigmentosa, when in trans with another pathogenic variant (Valverde et al, 2006; Shroyer et al, 2001). Shroyer et al. (2001) showed very little protein from cells transfected with the W1408R and R1640W variants in cis; however, proteins bearing only the W1408R or the R1640W variants appear to have mild or moderate defects in expression or stability. Sun et al. (2000) showed the W1408R variant had reduced basal ATPase activity compared to wild-type. The W1408R 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. The W1408R variant 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. We interpret W1408R as a pathogenic variant.
Eurofins Ntd Llc (ga)	RCV000085613	SCV000339313	other	not provided	2017-08-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085613	SCV001230608	pathogenic	not provided	2024-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1408 of the ABCA4 protein (p.Trp1408Arg). This variant is present in population databases (rs61750135, gnomAD 0.004%). This missense change has been observed in individual(s) with ABCA4-related conditions (PMID: 9973280, 28559085, 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: 99260). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087, 11687513). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000210333	SCV001239107	pathogenic	Retinal dystrophy	2019-06-16	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000408501	SCV001573565	pathogenic	Severe early-childhood-onset retinal dystrophy	2021-04-08	criteria provided, single submitter	research	The ABCA4 c.4222T>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PM1, PM3-S. Based on this evidence we have classified this variant as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000408501	SCV002557387	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200), cone-rod dystrophy 3 (MIM#604116), 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 tryptophan to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. One variant (p.(Trp1408Leu)), has been reported as a VUS but also observed in several compound heterozygous individuals with STGD (ClinVar, PMID: 10206579, PMID: 25066811). Another variant (p.(Trp2408Cys)) has also been observed in an individual with STGD (PMID: 30903310). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and is commonly observed in cis with another missense variant (p.(Arg1640Trp)). However, it has also been observed in at least four unrelated families with Stargardt disease (STGD), in the absence of p.(Arg1640Trp) (PMID: 9973280, PMID: 29925512). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been observed to segregate in a family with four compound heterozygous siblings with STGD (PMID: 9973280). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected HEK293 cells resulted in mild-moderate reductions in protein expression and enzyme activity (PMID: 11017087, PMID: 11687513). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Retina International	RCV000085613	SCV000117752	not provided	not provided		no assertion provided	not provided
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000210333	SCV000259104	pathogenic	Retinal dystrophy	2015-01-30	no assertion criteria provided	clinical testing
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV000408501	SCV005047011	pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research