ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs61748520
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000085811 SCV000344273 pathogenic not provided 2016-08-29 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000318700 SCV001164561 likely pathogenic Severe early-childhood-onset retinal dystrophy 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, http://gnomad.broadinstitute.org; 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).
Labcorp Genetics (formerly Invitae), Labcorp RCV000085811 SCV001230709 pathogenic not provided 2024-08-02 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, gnomAD 0.004%). This variant has been observed in individual(s) with Stargardt disease (PMID: 23918662, 28041643). 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: 99452). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
Fulgent Genetics, Fulgent Genetics RCV002490746 SCV002783221 likely pathogenic Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 2021-10-08 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004529894 SCV004114590 likely pathogenic ABCA4-related disorder 2023-04-03 criteria provided, single submitter clinical testing The ABCA4 c.6342G>A variant is not predicted to result in an amino acid change (p.=). This variant has been reported in the compound heterozygous state in patients with Stargardt disease, and functional studies support its pathogenicity (Braun et al. 2013. PubMed ID: 23918662; Carss et al. 2016. PubMed ID: 28041643). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94466602-C-T). This variant is interpreted as likely pathogenic.
GeneDx RCV000085811 SCV005685550 pathogenic not provided 2024-07-24 criteria provided, single submitter clinical testing RNA studies demonstrate a damaging effect: a "leaky" splice defect resulting in an out-of-frame transcript (PMID: 23918662); Identified in patients with ABCA4-related disorders in published literature (PMID: 28041643, 38219857); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 21911583, 23918662, 36284670, 35120629, 31964843, 32581362, 28041643, 38219857)
Retina International RCV000085811 SCV000117954 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000318700 SCV000599016 likely pathogenic Severe early-childhood-onset retinal dystrophy 2015-01-01 no assertion criteria provided research

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