Submissions for variant NM_000350.3(ABCA4):c.4363T>C (p.Cys1455Arg)

gnomAD frequency: 0.00001  dbSNP: rs758835368

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443223	SCV000511896	likely pathogenic	not provided	2019-10-18	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21911583, 20647261, 29925512, 28559085, 29126757, 17982420, 24020726, 25324290, 23499370, 29343940, 29310964, 28041643, 22449572, 25312043, 27699414, 32581362)
Illumina Laboratory Services, Illumina	RCV000779004	SCV000915445	likely pathogenic	ABCA4-related disorder	2018-12-06	criteria provided, single submitter	clinical testing	The ABCA4 c.4363T>C (p.Cys1455Arg) missense variant has been reported in at least six studies in which it is found in a total of seven individuals with Stargardt disease including in four individuals in a compound heterozygous state and in two individuals in a heterozygous state. The variant was also found in one individual with early onset macular degeneration in a heterozygous state (Rosenberg et al. 2007; Westeneng-van Haaften et al. 2012; Fujinami et al. 2013, Fujinami et al. 2014, Fujinami et al. 2015; Lambertus et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00003 in the European (non-Finnish) population from the Genome Aggregation Database. Based on the evidence, the p.Cys1455Arg variant is classified as pathogenic for ABCA4-related disorders.
Blueprint Genetics	RCV001075739	SCV001241369	pathogenic	Retinal dystrophy	2019-05-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000443223	SCV001373506	pathogenic	not provided	2024-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1455 of the ABCA4 protein (p.Cys1455Arg). This variant is present in population databases (rs758835368, gnomAD 0.003%). This missense change has been observed in individuals with Stargardt disease (PMID: 17982420, 22449572, 25312043, 29343940, 30834176, 32581362). ClinVar contains an entry for this variant (Variation ID: 377404). 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%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005027483	SCV005659790	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-06-10	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505057	SCV000598974	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research
Eurofins Ntd Llc (ga)	RCV000443223	SCV000705133	uncertain significance	not provided	2017-02-23	flagged submission	clinical testing