ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1648G>A (p.Gly550Arg) (rs61748558)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085413 SCV000321338 likely pathogenic not provided 2016-05-26 criteria provided, single submitter clinical testing The G550R variant has been published in association with ABCA4-related disorders (Shroyer et al., 2001; Stenirri et al., 2004). The G550R 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 G550R 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 where amino acids with similar properties to Glycine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Molecular Diagnostics Laboratory, M Health: University of Minnesota RCV000761253 SCV000891210 likely pathogenic Retinitis pigmentosa 19 2017-08-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763048 SCV000893529 likely pathogenic Cone-rod dystrophy 3; Age-related macular degeneration 2; Stargardt disease 1; Retinitis pigmentosa 19 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778263 SCV000914435 likely pathogenic ABCA4-Related Disorders 2018-10-25 criteria provided, single submitter clinical testing The ABCA4 c.1648G>A (p.Gly550Arg) missense variant has been identified in at least seven studies in which it is found in a total of seven individuals including in three in a compound heterozygous state with a known pathogenic variant and four in a heterozygous state with an undetected second allele (Shroyer et al., 2001; Briggs et al., 2001; Stenirri et al., 2004; Thiadens et al 2012; Bertelsen et al. 2014; Fujinami et al., 2015; Salles et al. 2018). Six of these individuals exhibited Stargardt disease and the seventh exhibited generalized choriocapillaris dystrophy. The p.Gly550Arg variant was absent from 100 control chromosomes (Shroyer et al., 2001) and is reported at a frequency of 0.00006 in the South Asian population of the Exome Aggregation Consortium, but this is based on one allele, so the variant is presumed to be rare. Based on the evidence, the p.Gly550Arg variant is classified as likely pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
The Cell Therapy Center,The University of Jordan RCV000782281 SCV000920582 pathogenic Cone-rod dystrophy 3 2019-03-15 criteria provided, single submitter research This variant was classified as pathogenic based on its segregation with the disease, allele frequency, and in-silico tools. One patient with this variant was found to have sectoral RP features.
Blueprint Genetics RCV001074836 SCV001240436 pathogenic Retinal dystrophy 2019-07-23 criteria provided, single submitter clinical testing
Invitae RCV000085413 SCV001401167 pathogenic not provided 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 550 of the ABCA4 protein (p.Gly550Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs61748558, ExAC 0.006%). This variant has been observed in individual(s) with Stargardt disease (PMID: 11726554, 28559085, 29925512). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99070). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Retina International RCV000085413 SCV000117550 not provided not provided no assertion provided not provided

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