ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.6342G>A (p.Val2114=) (rs61748520)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000085811 SCV000344273 pathogenic not provided 2016-08-29 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000318700 SCV001164561 likely pathogenic Stargardt disease 1 2018-12-03 criteria provided, single submitter research The heterozygous c.6342G>A variant in ABCA4 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with Stargardt disease. The presence of this variant in combination with a likely pathogenic variant increases the likelihood that the c.6342G>A variant is pathogenic. This variant has been identified in 0.001804% (5/277140) of chromosomes and by the Genome Aggregation Database (gnomAD,; dbSNP rs61748520). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies with keratinocytes from a patient with the variant in the heterozygous state provide some evidence that the c.6342G>A variant may impact protein function by creating a premature donor splice site, causing exon skipping of Exon 46 (PMID: 23918662). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, the c.6342G>A variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3, PM3_Supporting (Richards 2015).
Invitae RCV000085811 SCV001230709 pathogenic not provided 2019-12-24 criteria provided, single submitter clinical testing This sequence change affects codon 2114 of the ABCA4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ABCA4 protein. This variant is present in population databases (rs61748520, ExAC 0.001%). This variant has been observed in individual(s) with Stargardt disease (PMID: 23918662, 28041643). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99452). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 23918662). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001073884 SCV001239448 pathogenic Retinal dystrophy 2018-04-24 criteria provided, single submitter clinical testing
Retina International RCV000085811 SCV000117954 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000318700 SCV000599016 likely pathogenic Stargardt disease 1 2015-01-01 no assertion criteria provided research

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