ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.6221G>T (p.Gly2074Val)

dbSNP: rs367839100
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000850519 SCV000992723 likely pathogenic Cone-rod dystrophy 3; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 2018-10-12 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074418 SCV001240000 uncertain significance Retinal dystrophy 2019-08-16 criteria provided, single submitter clinical testing
Invitae RCV001234782 SCV001407441 pathogenic not provided 2023-11-22 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2074 of the ABCA4 protein (p.Gly2074Val). This variant is present in population databases (rs367839100, gnomAD 0.03%). This missense change has been observed in individuals with Stargardt disease (PMID: 23419329, 25082885, 29925512; Invitae). ClinVar contains an entry for this variant (Variation ID: 689736). 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%. This variant disrupts the p.Gly2074 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 25412400), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262439 SCV001440312 uncertain significance Cone-rod dystrophy 3 2019-01-01 criteria provided, single submitter clinical testing
3billion RCV002051899 SCV002318721 likely pathogenic Severe early-childhood-onset retinal dystrophy 2022-03-22 criteria provided, single submitter clinical testing A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001071049, PMID:25412400,18652558). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.994>=0.6, 3CNET: 0.996>=0.75). A missense variant is a common mechanism associated with Stargardt disease 1. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000358 ).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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