Submissions for variant NM_000350.3(ABCA4):c.926C>G (p.Pro309Arg) (rs61748545)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085874	SCV000321334	likely pathogenic	not provided	2018-10-18	criteria provided, single submitter	clinical testing	The P309R variant in the ABCA4 gene has been reported previously in association with autosomal recessive Stargardt disease when present with another disease-causing variant in the ABCA4 gene (Briggs et al., 2001; Cideciyan et al., 2009; Zernant et al., 2014; Carss et al., 2017). The P309R variant is observed in 39/24,022 (0.1624%) alleles from individuals of African background in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The P309R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P309R as a likely pathogenic variant.
Blueprint Genetics	RCV001075838	SCV001241477	likely pathogenic	Retinal dystrophy	2019-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV000085874	SCV001382437	uncertain significance	not provided	2019-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces proline with arginine at codon 309 of the ABCA4 protein (p.Pro309Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs61748545, ExAC 0.2%). This variant has been observed in individuals with Stargardt disease (PMID: 25066811, 22247458) and in an individual with macular dystrophy (PMID: 28041643). ClinVar contains an entry for this variant (Variation ID: 99513). 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	RCV000085874	SCV000118017	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504769	SCV000599027	likely pathogenic	Macular dystrophy	2015-01-01	no assertion criteria provided	research

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