ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1319A>G (p.Tyr440Cys)

gnomAD frequency: 0.00003  dbSNP: rs770439859
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000330893 SCV000359511 uncertain significance Stargardt Disease, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000387710 SCV000359512 uncertain significance Cone-Rod Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000295678 SCV000359513 uncertain significance Retinitis Pigmentosa, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000343633 SCV000359514 uncertain significance Macular degeneration 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000523526 SCV000617270 uncertain significance not provided 2017-08-07 criteria provided, single submitter clinical testing The Y440C variant in the ABCA4 gene has been previously reported in the heterozygous state in an individual with cone rod dystrophy (Bauwens et al., 2015). While not observed in the homozygous state, the Y440C variant is observed in 20/16512 (0.12%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). The Y440C 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. 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. We interpret Y440C as a variant of uncertain significance.
Illumina Laboratory Services, Illumina RCV001102042 SCV001258690 uncertain significance ABCA4-related disorder 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV000523526 SCV002205956 uncertain significance not provided 2022-07-31 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 440 of the ABCA4 protein (p.Tyr440Cys). This variant is present in population databases (rs770439859, gnomAD 0.1%). This missense change has been observed in individual(s) with cone-rod dystrophy (PMID: 25346251). ClinVar contains an entry for this variant (Variation ID: 298262). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV004816525 SCV005072187 likely pathogenic Retinal dystrophy 2014-01-01 criteria provided, single submitter clinical testing

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