ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.2966T>C (p.Val989Ala) (rs61749454)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085529 SCV000321347 likely pathogenic not provided 2018-08-03 criteria provided, single submitter clinical testing The V989A missense change in the ABCA4 gene has been previously published in association with Stargardt disease (Zernant et al., 2014; Briggs et al., 2001; Huang et al., 2014). The NHLBI Exome Sequencing Project reports V989A was observed in 11/4406 (0.25%) alleles from individuals of African American background, indicating it may be a rare variant in this population. Additionally, the 1000 Genomes Project Consortium reports V989A was observed in 8/1322 (0.61%) alleles of African origin. The 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 within the nucleotide-binding domain 1 where amino acids with similar properties to Valine are tolerated across species, and 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 nearby residues (G991R/V) 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000085529 SCV000339698 uncertain significance not provided 2016-02-22 criteria provided, single submitter clinical testing
Invitae RCV000085529 SCV001202798 pathogenic not provided 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 989 of the ABCA4 protein (p.Val989Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs61749454, ExAC 0.3%). This variant has been observed in individual(s) with ABCA4-related retinal disease (PMID: 22247458, 28327576, 25066811, 23755871, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99180). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C2). This variant disrupts the p.Val989 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 29641573), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074424 SCV001240007 pathogenic Retinal dystrophy 2019-08-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085529 SCV001249472 pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing
Retina International RCV000085529 SCV000117666 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504904 SCV000598956 likely pathogenic Stargardt disease 1 2015-01-01 no assertion criteria provided research

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