ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.5338C>G (p.Pro1780Ala)

gnomAD frequency: 0.00014  dbSNP: rs121909207
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000778999 SCV000915440 uncertain significance ABCA4-Related Disorders 2018-11-19 criteria provided, single submitter clinical testing The ABCA4 c.5338C>G (p.Pro1780Ala) missense variant has been reported in one study in which it is found in one individual with Stargardt disease in a compound heterozygous state (Shroyer et al., 2000). The variant has not been reported in the literature in association with any other disease. The p.Pro1780Ala variant was absent from 101 control individuals and is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Pro1780Ala variant is classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen RCV000994036 SCV001147328 likely pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing
Invitae RCV000994036 SCV001208557 pathogenic not provided 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1780 of the ABCA4 protein (p.Pro1780Ala). This variant is present in population databases (rs121909207, gnomAD 0.02%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 10746567, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7912). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001073346 SCV001238886 uncertain significance Retinal dystrophy 2018-12-12 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000008373 SCV002059863 uncertain significance Severe early-childhood-onset retinal dystrophy 2018-09-04 criteria provided, single submitter clinical testing
GeneDx RCV000994036 SCV002578261 uncertain significance not provided 2023-04-26 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20849526, 28559085, 32531858, 10746567, 35886001)
MGZ Medical Genetics Center RCV000008373 SCV002580796 uncertain significance Severe early-childhood-onset retinal dystrophy 2022-02-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003317029 SCV004020572 uncertain significance not specified 2023-06-06 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.5338C>G (p.Pro1780Ala) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251452 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Stargardt Disease (0.00011 vs 0.0014), allowing no conclusion about variant significance. c.5338C>G has been reported in the literature as a compound heterozygous genotype in individuals affected with Stargardt Disease (e.g. Shroyer_2000, Stone_2017, Weisschuh_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35886001, 10746567, 28559085, 32531858). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) or pathogenic (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until additional clinical and/or functional data becomes available.
OMIM RCV000008373 SCV000028581 pathogenic Severe early-childhood-onset retinal dystrophy 2000-02-01 no assertion criteria provided literature only

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