ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408555 SCV000281922 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
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.

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