ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.2023G>A (p.Val675Ile)

gnomAD frequency: 0.00001  dbSNP: rs575453437
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000478104 SCV000342424 likely pathogenic not provided 2016-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000478104 SCV000564522 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing The V675I variant has been reported previously in association with ABCA4-related disorders (Duncker et al., 2015; Fujinami et al., 2013) with limited evidence to support pathogenicity. The V675I variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The V675I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. However, another missense variant in a nearby residue (K678N) have been reported in the Human Gene Mutation Database in association with ABCA4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
CeGaT Center for Human Genetics Tuebingen RCV000478104 SCV000608480 likely pathogenic not provided 2017-04-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074658 SCV001240250 likely pathogenic Retinal dystrophy 2019-02-22 criteria provided, single submitter clinical testing
Invitae RCV000478104 SCV001421498 pathogenic not provided 2021-11-27 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 675 of the ABCA4 protein (p.Val675Ile). This variant is present in population databases (rs575453437, gnomAD 0.04%). This missense change has been observed in individuals with Stargardt disease (PMID: 23499370, 26593885, 28041643, 30060493). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 288341). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000329208 SCV000598947 likely pathogenic Severe early-childhood-onset retinal dystrophy 2015-01-01 no assertion criteria provided research

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