ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.5318C>T (p.Ala1773Val) (rs760549861)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408555 SCV000281922 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000441041 SCV000511907 likely pathogenic not provided 2016-01-05 criteria provided, single submitter clinical testing The A1773V variant has been reported previously in association with Stargardt disease (Stenirri et al., 2008; Chacon-Camacho et al., 2013; Duncker et al., 2015). The Chacon-Camacho study presents evidence of a possible founder effect of A1773V in the Mexican population, based on its presence in 8/46 mutant alleles (17%) in their small population of only 31 subjects. The A1773V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A1773V 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 that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same residue (A1773E) and in nearby residues (Y1770D, I1775N, P1776L) 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. Therefore, this variant is likely pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826133 SCV000967649 pathogenic Stargardt disease 2018-06-05 criteria provided, single submitter clinical testing The p.Ala1773Val variant in ABCA4 has been reported in >10 individuals with Star gardt disease and/or retinal degeneration, including at least 3 compound heteroz ygotes and 6 homozygotes, and segregated in 4 affected relatives (Stenirri 2008, Chacon-Camacho 2013, Duncker 2015, Biswas 2017, Lopez-Rubio 2018). This variant has been reported in ClinVar (Variation ID: 236129) and has been identified in 0.05% (16/33582) of Latino chromosomes by the Genome Aggregation Database (gnomA D, http://gnomad.broadinstitute.org/; dbSNP rs760549861). Although this variant is seen in the general population, its frequency is consistent with a recessive carrier frequency. Additionally, another allele the same position (p.Ala1773Glu) has been reported with a similar phenotype (Downes 2012), suggesting that chang es at this position may not be tolerated. In summary, this variant is pathogenic for Stargardt disease in an autosomal recessive manner. ACMG/AMP Criteria appli ed: PM3_VeryStrong; PP1_Moderate; PP3.
Invitae RCV000441041 SCV001232188 pathogenic not provided 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1773 of the ABCA4 protein (p.Ala1773Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs760549861, ExAC 0.1%). This variant has been observed in many individuals and families with ABCA4-related retinal disease and has been proposed to be a founder variant in the Mexican population (PMID: 18652558, 29422768, 23419329, 28130426). ClinVar contains an entry for this variant (Variation ID: 236129). 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 RCV001074401 SCV001239981 pathogenic Retinal dystrophy 2019-08-09 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000441041 SCV001247607 pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000826133 SCV001337920 pathogenic Stargardt disease 2020-01-08 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.5318C>T (p.Ala1773Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251426 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ABCA4 causing Stargardt disease (7.6e-05 vs 0.0014), allowing no conclusion about variant significance. c.5318C>T has been reported in the literature in numerous individuals affected with Stargardt disease (homozygotes and heterozygotes) and may be a Mexican founder mutation (Chacon-Camacho_2013, Fujinami_2019, Lopez-Rubio_2018, Stenirri_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharon lab,Hadassah-Hebrew University Medical Center RCV000826133 SCV001160831 likely pathogenic Stargardt disease 2019-06-23 no assertion criteria provided research

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