ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.3607G>A (p.Gly1203Arg) (rs1064793011)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479551 SCV000564531 likely pathogenic not provided 2013-12-29 criteria provided, single submitter clinical testing The G1203R missense change in the ABCA4 gene has been reported in association with ABCA4-related disorders (Stenirri et al., 2004). However, no functional data was provided and the patient that is reported also harbored the K223Q and S1071L variants. The G1203R amino acid substitution is non-conservative with a neutral non-polar residue (Gly) being replaced by a positively charged residue (Arg). This residue at which this substitution occurs is highly conserved among species. This missense change affects the last base of the exon and is predicted to impact normal splicing. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. Other missense variants at this residue (G1203D and G1203E) have been reported in association with ABCA4-related disorders (Kitiratschky et al., 2008; Stenirri et al., 2004). Therefore, based on the information currently available, G1203R is a strong candidate for a pathogenic variant; however, the possibility that it is a benign variant cannot be excluded.
Blueprint Genetics RCV001073935 SCV001239500 uncertain significance Retinal dystrophy 2018-07-16 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001101857 SCV001258498 uncertain significance ABCA4-Related Disorders 2017-09-17 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV000479551 SCV001413553 uncertain significance not provided 2019-11-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1203 of the ABCA4 protein (p.Gly1203Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 24 of the ABCA4 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Stargardt disease (PMID: 15192030). ClinVar contains an entry for this variant (Variation ID: 417989). 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 29162642). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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