Submissions for variant NM_000350.3(ABCA4):c.6229C>T (p.Arg2077Trp)

dbSNP: rs61750645

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000402409	SCV000281951	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000085797	SCV000336497	pathogenic	not provided	2015-10-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000085797	SCV000490383	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29555955, 19217903, 28041643, 29847635, 9054934, 9973280, 10958763, 18285826, 24713488, 28559085, 29925512, 20647261, 32581362, 32619608)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004998	SCV001164556	likely pathogenic	Cone-rod dystrophy 3	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Arg2077Trp variant in ABCA4 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with cone-rod dystrophy. The presence of this variant in combination with a likely pathogenic variant and in an individual with cone-rod dystrophy increases the likelihood that the p.Arg2077Trp variant is pathogenic. This variant has been identified in 0.0004062% (1/246206) of chromosomes and by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs61750645). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with an additional reported pathogenic variant (ClinVar Variation ID: 7904) and a reported likely pathogenic variant (ClinVar Variation ID: 99224) in two individuals with ABCA4-related disease reported in the literature increases the likelihood that the p.Arg2077Trp variant is pathogenic (PMID: 23755871, 18285826). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM3_Strong (Richards 2015).
Invitae	RCV000085797	SCV001205032	pathogenic	not provided	2023-07-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 29847635). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2077 of the ABCA4 protein (p.Arg2077Trp). This variant is present in population databases (rs61750645, gnomAD 0.0009%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99438). 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.
Blueprint Genetics	RCV000504630	SCV001239102	pathogenic	Retinal dystrophy	2019-06-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085797	SCV001247596	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Very Strong, PM2, PP3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085797	SCV001447784	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Retina International	RCV000085797	SCV000117940	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504630	SCV000599012	likely pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787519	SCV000926487	likely pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV001770079	SCV002011790	uncertain significance	Age related macular degeneration 2	2021-08-04	no assertion criteria provided	clinical testing