ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.656G>C (p.Arg219Thr) (rs61748537)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408468 SCV000281809 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085831 SCV000321331 likely pathogenic not provided 2016-02-15 criteria provided, single submitter clinical testing The R219T likely pathogenic variant has been reported in association with Stargardt disease (Rosenberg et al., 2007; Kellner et al., 2009; Lambertus et al, 2015), with limited evidence regarding pathogenicity. The R219T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R219T 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 not conserved, 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 (R220C, G221R) have been reported in the Human Gene Mutation Database in association with Stargardt (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085831 SCV000608486 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073757 SCV001239317 uncertain significance Retinal dystrophy 2017-11-29 criteria provided, single submitter clinical testing
Invitae RCV000085831 SCV001403273 uncertain significance not provided 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 219 of the ABCA4 protein (p.Arg219Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant is present in population databases (rs61748537, ExAC 0.008%). This variant has been observed in individuals affected with ABCA4-related disease who also had 2 or more other variants in ABCA4, making the contribution of this variant unclear (PMID: 26720470, 29555955, 19243736, 25444351, 28118664). ClinVar contains an entry for this variant (Variation ID: 99470). 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 C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Retina International RCV000085831 SCV000117974 not provided not provided no assertion provided not provided

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