ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.161G>A (p.Cys54Tyr) (rs150774447)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000210980 SCV000267673 likely pathogenic Stargardt disease 1 criteria provided, single submitter research identified in compound heterozygous state in affected individual/s with macular isease
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000210980 SCV000281799 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085408 SCV000321323 likely pathogenic not provided 2018-02-27 criteria provided, single submitter clinical testing The C54Y variant in the ABCA4 gene has been reported previously in the homozygous and compound heterozygous states in association with Stargardt disease (Zhang et al., 1999; Aleman et al., 2007; Alapati et al., 2014; Zhao et al., 2015). The C54Y variant is observed in 9/126642 (0.007%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The C54Y variant 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. We interpret C54Y as a likely pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000085408 SCV000336475 pathogenic not provided 2016-12-05 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826094 SCV000967596 likely pathogenic Stargardt disease 2017-11-22 criteria provided, single submitter clinical testing The p.Cys54Tyr (NM_000350.2 c.161G>A) variant in ABCA4 has been reported in at l east 6 compound heterozygotes, 1 homozygote, and 6 individuals without a second pathogenic variant listed, all who had ABCA4-associated retinal degenerations or Stargardt disease (Lewis 1999, Zhang 1999, Aleman 2007, Cella 2009, Fujinami 20 13, Alipati 2014, and Zhao 2015). This variant also segreagated with disease in 3 individuals. This variant has been reported in ClinVar (Variation ID#99065) an d has been identified in 0.007% (9/126642) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1507744 47). Although this variant has been seen in the general population, its frequenc y is low enough to be consistent with a recessive carrier frequency. Computation al prediction tools and conservation analysis suggest that the p.Cys54Tyr varian t may impact the protein, though this information is not predictive enough to de termine pathogenicity. In summary, although additional studies are required to f ully establish its clinical significance, the p.Cys54Tyr variant is likely patho genic for Stargardt disease in an autosomal recessive manner based on its occurr ence in individuals with this disease. ACMG/AMP Criteria applied: PM3_Strong; PM 2; PP1; PP3 (Richards 2015).
Invitae RCV000085408 SCV001211642 pathogenic not provided 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 54 of the ABCA4 protein (p.Cys54Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs150774447, ExAC 0.01%). This variant has been observed in many individuals and families with Stargardt disease (PMID: 10612508, 10634594, 11846518, 11726554, 19074458). ClinVar contains an entry for this variant (Variation ID: 99065). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Retina International RCV000085408 SCV000117545 not provided not provided no assertion provided not provided

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