ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4363T>C (p.Cys1455Arg) (rs758835368)

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Total submissions: 6
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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)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000443223 SCV000705133 uncertain significance not provided 2017-02-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779004 SCV000915445 likely pathogenic ABCA4-Related Disorders 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
Invitae RCV000443223 SCV001373506 likely pathogenic not provided 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 1455 of the ABCA4 protein (p.Cys1455Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs758835368, ExAC 0.003%). This variant has been observed in individuals affected with Stargardt disease (PMID: 22449572, 25312043, 29343940, 30834176). ClinVar contains an entry for this variant (Variation ID: 377404). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505057 SCV000598974 likely pathogenic Stargardt disease 1 2015-01-01 no assertion criteria provided research

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