ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.2453G>A (p.Gly818Glu)

gnomAD frequency: 0.00006  dbSNP: rs61750202
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085479 SCV000511886 pathogenic not provided 2023-03-09 criteria provided, single submitter clinical testing Published functional studies demonstrate impaired substrate binding capacity and limited substrate release after ATP binding (Garces et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23419329, 9054934, 28044389, 14709597, 11328725, 9973280, 29925512, 30718709, 11017087, 33375396)
Labcorp Genetics (formerly Invitae), Labcorp RCV000085479 SCV001200235 pathogenic not provided 2025-01-18 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 818 of the ABCA4 protein (p.Gly818Glu). This variant is present in population databases (rs61750202, gnomAD 0.2%). This missense change has been observed in individual(s) with ABCA4-related retinal dystrophy (PMID: 9054934, 9973280, 10090887, 14709597, 23419329). 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: 99135). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075477 SCV001241100 pathogenic Retinal dystrophy 2018-10-23 criteria provided, single submitter clinical testing
3billion, Medical Genetics RCV002250561 SCV002521204 pathogenic Severe early-childhood-onset retinal dystrophy 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.019%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.41). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099135). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 17982420, 23419329). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Retina International RCV000085479 SCV000117616 not provided not provided no assertion provided not provided
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000787774 SCV000926780 likely pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research

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