ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.6119G>A (p.Arg2040Gln)

gnomAD frequency: 0.00024  dbSNP: rs148460146
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000132592 SCV000490382 likely pathogenic not provided 2023-07-23 criteria provided, single submitter clinical testing 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: 25066811, 31054281, 22449572, 26780318, 25474345, 28890726, 29343940, 31589614, 32531858, 34721897, 33301772, 35657619, 33261146, 34758253)
Mendelics RCV000986347 SCV001135325 likely pathogenic Severe early-childhood-onset retinal dystrophy 2020-01-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073482 SCV001239025 pathogenic Retinal dystrophy 2019-03-29 criteria provided, single submitter clinical testing
Invitae RCV000132592 SCV001374374 pathogenic not provided 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2040 of the ABCA4 protein (p.Arg2040Gln). This variant is present in population databases (rs148460146, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with Stargardt disease (PMID: 22449572, 25066811, 25474345, 26780318). ClinVar contains an entry for this variant (Variation ID: 143076). 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%. For these reasons, this variant has been classified as Pathogenic.
3billion RCV000986347 SCV002521807 likely 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: 0.031%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.73). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143076). A different missense change at the same codon (p.Arg2040Pro) has been reported to be associated with ABCA4 related disorder (ClinVar ID: VCV000806157). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Dept Of Ophthalmology, Nagoya University RCV001073482 SCV004706425 likely pathogenic Retinal dystrophy 2023-10-01 criteria provided, single submitter research
Department of Ophthalmology and Visual Sciences Kyoto University RCV000132592 SCV000172537 probable-non-pathogenic not provided no assertion criteria provided not provided Converted during submission to Likely benign.
Genomics England Pilot Project, Genomics England RCV001542554 SCV001760042 likely pathogenic Retinitis pigmentosa 19 no assertion criteria provided clinical testing

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