ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.3259G>A (p.Glu1087Lys)

gnomAD frequency: 0.00001  dbSNP: rs61751398
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000085562 SCV001228211 pathogenic not provided 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1087 of the ABCA4 protein (p.Glu1087Lys). This variant is present in population databases (rs61751398, gnomAD 0.01%). This missense change has been observed in individual(s) with Stargardt disease, Leber congenital amaurosis, or cone-rod dystrophy (PMID: 9054934, 19265867, 22264887, 28559085, 30576320). 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: 99211). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075833 SCV001241472 pathogenic Retinal dystrophy 2019-07-25 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000085562 SCV001249468 pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001199228 SCV001370265 pathogenic Age related macular degeneration 2 2019-03-17 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP2,PP3. This variant was detected in homozygous state.
Kariminejad - Najmabadi Pathology & Genetics Center RCV001814057 SCV001755586 pathogenic Abnormality of the eye 2021-07-10 criteria provided, single submitter clinical testing
GeneDx RCV000085562 SCV001804262 pathogenic not provided 2021-11-12 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect with reduced protein expression and decreased ATPase activity (Sun et al., 2000); 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: 12824224, 22264887, 20128570, 11328725, 11702214, 11017087, 23883535, 9054934, 14709597, 27820952, 32845050, 29925512, 30204727, 32619608, 28559085, 30576320, 19265867)
3billion RCV001808323 SCV002058562 pathogenic Retinitis pigmentosa 19 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099211, PMID:9054934, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099212,VCV001068257, PMID:14517951,29925512, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.966, 3CNET: 0.994, PP3_P). A missense variant is a common mechanism associated with Retinitis pigmentosa 19 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology RCV002466427 SCV002761865 pathogenic Cone-rod dystrophy 3 2021-01-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002498455 SCV002813171 pathogenic Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 2021-09-24 criteria provided, single submitter clinical testing
Retina International RCV000085562 SCV000117699 not provided not provided no assertion provided not provided

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