Submissions for variant NM_000350.3(ABCA4):c.214G>A (p.Gly72Arg)

gnomAD frequency: 0.00001  dbSNP: rs61751412

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000882	SCV001157964	likely pathogenic	not specified	2019-01-03	criteria provided, single submitter	clinical testing	The ABCA4 c.214G>A; p.Gly72Arg variant (rs617514127) is published in the medical literature in individuals with Stargardt or ABCA4-related disease in the compound heterozygous or homozygous state (Birtel 2018, Garces 2018, Khan 2018, Rivera 2000, Rosenberg 2007). The variant is reported in the ClinVar database (Variation ID: 99120) and in the general population with an allele frequency of 0.003% (7/251414 alleles) in the Genome Aggregation Database. The glycine at this position is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. In support of this prediction, experiments show reduced binding and ATPase activity compared to the wild type protein (Garces 2018). Considering available evidence, this variant is classified as likely pathogenic. References: Birtel J et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018 Mar 19;8(1):4824. Garces F et al. Correlating the Expression and Functional Activity of ABCA4 Disease Variants With the Phenotype of Patients With Stargardt Disease. Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2305-2315. Khan KN et al. Early Patterns of Macular Degeneration in ABCA4-Associated Retinopathy. Ophthalmology. 2018 May;125(5):735-746. Rivera A et al. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet. 2000 Oct;67(4):800-13. Rosenberg T et al. N965S is a common ABCA4 variant in Stargardt-related retinopathies in the Danish population. Mol Vis. 2007 Oct 17;13:1962-9.
CeGaT Center for Human Genetics Tuebingen	RCV000085464	SCV001247764	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085464	SCV001446806	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV001353042	SCV001548161	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
Invitae	RCV000085464	SCV001590830	pathogenic	not provided	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 72 of the ABCA4 protein (p.Gly72Arg). This variant is present in population databases (rs61751412, gnomAD 0.02%). This missense change has been observed in individual(s) with inherited retinal disease (PMID: 22264887, 28355279, 30834176, 30945053). 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: 99120). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 29847635). For these reasons, this variant has been classified as Pathogenic.
Arcensus	RCV002466250	SCV002564567	likely pathogenic	Age related macular degeneration 2	2013-02-01	criteria provided, single submitter	clinical testing
Retina International	RCV000085464	SCV000117601	not provided	not provided		no assertion provided	not provided
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787776	SCV000926783	likely pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research