ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1253T>C (p.Phe418Ser) (rs794726979)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000173679 SCV000321336 likely pathogenic not provided 2018-08-06 criteria provided, single submitter clinical testing The F418S variant has been reported in association with ABCA4-related disorders (Zernant et al., 2011; Downes et al., 2012; Fujinami et al., 2013; Müller et al., 2015). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). F418S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. In summary, we consider this variant to be likely pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000173679 SCV000331703 pathogenic not provided 2016-08-29 criteria provided, single submitter clinical testing
Invitae RCV000173679 SCV001205468 pathogenic not provided 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 418 of the ABCA4 protein (p.Phe418Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with ABCA4-related conditions (PMID: 30834176, 28341476, 29555955, 28559085, 21911583). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 193580). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001073557 SCV001239106 pathogenic Retinal dystrophy 2019-06-15 criteria provided, single submitter clinical testing

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