Submissions for variant NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp)

gnomAD frequency: 0.00003  dbSNP: rs61751404

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg	RCV000408519	SCV000281907	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085683	SCV000321353	pathogenic	not provided	2018-10-04	criteria provided, single submitter	clinical testing	The R1640W pathogenic variant in the ABCA4 gene has been reported previously in autosomal recessive Stargardt disease in affected individuals when in the homozgyous state or when in trans with another pathogenic variant (Battu et al., 2015; Fujinami et al., 2013; Rozet et al., 1998). The R1640W variant has been reported on the same allele (in cis) with the W1408R 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. The R1640W 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 R1640W 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 R1640W as a pathogenic variant.
Eurofins NTD LLC (GA)	RCV000085683	SCV000339315	other	not provided	2017-08-31	criteria provided, single submitter	clinical testing
Invitae	RCV000085683	SCV001210838	pathogenic	not provided	2021-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1640 of the ABCA4 protein (p.Arg1640Trp). This variant is present in population databases (rs61751404, gnomAD 0.007%). This missense change has been observed in individuals with ABCA4-related conditions (PMID: 9781034, 28041643, 28559085, 29925512). ClinVar contains an entry for this variant (Variation ID: 99330). 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. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11687513). This variant disrupts the p.Arg1640 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10711710, 11527935, 23755871, 26103963, 28118664). 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.
Blueprint Genetics	RCV000210311	SCV001239246	pathogenic	Retinal dystrophy	2019-08-16	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085683	SCV001447306	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000408519	SCV001573564	pathogenic	Severe early-childhood-onset retinal dystrophy	2021-04-08	criteria provided, single submitter	research	The ABCA4 c.4918C>T 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.
Molecular Genetics, Royal Melbourne Hospital	RCV000408519	SCV002503642	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace arginine with tryptophan at codon 1640 of the ABCA4 protein, p.(Arg1640Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and there is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.003%, consistent with recessive disease (rs61751404, 8/251,420 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in the homozygous state and compound heterozygous with a second pathogenic allele in multiple Stargardt disease cases (PMID: 9781034, 10090887, 11687513, 21873672). The missense change causes reduced protein expression and ATPase activity in in vitro functional assays (PMID: 11687513). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). A different missense change at the same amino acid residue (p.Arg1640Gln) determined to be pathogenic has been seen before (ClinVar ID: 99331). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC . Following criteria are met: PM3_Strong, PM2, PM5, PS3_Supporting, PP3.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute	RCV000408519	SCV002558011	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 arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (8 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (8 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 in the annotated ABC2_membrane_3 domain (Protein DataBank). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals diagnosed with Stargardt disease (ClinVar, PMIDs: 23769331, 25066811, 25922843, 29854428, 30060493, 30834176, 31766579). (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	RCV000085683	SCV000117823	not provided	not provided		no assertion provided	not provided
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals	RCV000210311	SCV000259103	pathogenic	Retinal dystrophy	2015-01-30	no assertion criteria provided	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505114	SCV000598986	likely pathogenic	Leber congenital amaurosis	2015-01-01	no assertion criteria provided	research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet	RCV000787504	SCV000926470	pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research
Sharon lab,Hadassah-Hebrew University Medical Center	RCV000787504	SCV001160839	pathogenic	Stargardt disease	2019-06-23	no assertion criteria provided	research