ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.5077G>A (p.Val1693Ile) (rs61750563)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085696 SCV000564537 likely pathogenic not provided 2018-08-21 criteria provided, single submitter clinical testing The V1693I variant has been published in association with ABCA4-related disorders (Webster et al., 2001; Mandal et al., 2005; September et al., 2004; Utz et al., 2013). The NHLBI Exome Sequencing Project reports V1693I was observed in 8/4406 (0.18%) alleles from individuals of African American background, and the 1000 Genomes Project Consortium reports V1693I was observed in 3/1322 (0.20%) alleles from individuals of African background and in 3/198 (1.5%) alleles from individuals in Kenya indicating it may be a rare variant in this population. However, there were no healthy homozygotes identified in these populations, which is what one would expect to see if the V1693I variant is benign. The V1693I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Other likely pathogenic missense variants in nearby residues (S1689P, S1696N, S1696R) have been reported in the Human Gene Mutation Database in association with ABCA4-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic.
Invitae RCV000085696 SCV001224157 uncertain significance not provided 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1693 of the ABCA4 protein (p.Val1693Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs61750563, ExAC 0.2%). This variant has been observed in individuals affected with Stargardt disease (PMID: 11328725, 24011517, 29925512, Invitae). ClinVar contains an entry for this variant (Variation ID: 99343). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Blueprint Genetics RCV001073371 SCV001238912 likely pathogenic Retinal dystrophy 2019-01-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085696 SCV001247609 uncertain significance not provided 2019-09-01 criteria provided, single submitter clinical testing
Retina International RCV000085696 SCV000117836 not provided not provided no assertion provided not provided

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