ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4326C>A (p.Asn1442Lys) (rs762150575)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480271 SCV000564534 likely pathogenic not provided 2015-02-23 criteria provided, single submitter clinical testing The N1442K variant that is likely pathogenic was identified in the ABCA4 gene. The N1442K missense change has been reported several times in association with Stargardt disease (Zernant et al., 2011; Downes et al., 2012; Fujinami et al., 2013). However, no segregation data or functional data was provided, and the assessment of pathogenicity was based on in silico predictors. The N1442K variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in an external variant database. The N1442K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. Missense variants in nearby residues (G1448R, R1443H, F1440S, F1440V) have been reported in the Human Gene Mutation Database in association with Stargardt disease and cone-rod dystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, the N1442K variant is a strong candidate for a pathogenic variant; however, the possibility that it is a benign variant cannot excluded.
Blueprint Genetics RCV001073593 SCV001239144 pathogenic Retinal dystrophy 2019-07-09 criteria provided, single submitter clinical testing
Invitae RCV000480271 SCV001375786 pathogenic not provided 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 1442 of the ABCA4 protein (p.Asn1442Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs762150575, ExAC 0.004%). This variant has been observed in combination with another ABCA4 variant in individual(s) with Stargardt disease or cone-rod dystrophy (PMID: 30834176, 23143460, 23982839, 28559085, Invitae). 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: 417991). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Asn1442 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 30060493), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787780 SCV000926788 likely pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research

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