Submissions for variant NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp) (rs61751404)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg	RCV000408519	SCV000281907	likely pathogenic	Stargardt disease 1	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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000085683	SCV000339315	other	not provided	2017-08-31	criteria provided, single submitter	clinical testing
Invitae	RCV000085683	SCV001210838	pathogenic	not provided	2020-06-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 1640 of the ABCA4 protein (p.Arg1640Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs61751404, ExAC 0.001%). This variant has been observed in many individuals affected with ABCA4-related conditions. While this variant is commonly found in cis with the variant p.Trp1408Arg, it has also been observed without p.Trp1408Arg in affected individuals (PMID: 28041643, 28559085, 29925512, 9781034). ClinVar contains an entry for this variant (Variation ID: 99330). This variant has been reported to affect ABCA4 protein 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: 11527935, 26103963, 23755871, 10711710, 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	Stargardt disease 1	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.
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