ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1222C>T (p.Arg408Ter)

gnomAD frequency: 0.00004  dbSNP: rs61748550
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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) RCV000085378 SCV000202093 pathogenic not provided 2016-03-21 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV000152707 SCV000281816 pathogenic Severe early-childhood-onset retinal dystrophy 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085378 SCV000329046 pathogenic not provided 2021-11-29 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23953153, 25525159, 28947085, 30771335, 16103129, 11846518, 23755871, 14709597, 11328725, 28118664, 23891399, 30060493, 33369172, 33301772, 32619608)
Blueprint Genetics RCV001074409 SCV001239991 pathogenic Retinal dystrophy 2019-08-11 criteria provided, single submitter clinical testing
Invitae RCV000085378 SCV001411328 pathogenic not provided 2024-01-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg408*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs61748550, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Stargardt disease or retinitis pigmentosa (PMID: 16103129, 23755871). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99035). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000085378 SCV001449006 pathogenic not provided 2017-06-26 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV002513925 SCV003761281 pathogenic Retinitis pigmentosa 19 2023-01-25 criteria provided, single submitter curation The heterozygous p.Arg408Ter variant in ABCA4 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 99288) and a known risk variant (ClinVar Variation ID: 99390), in one individual with retinal dystrophy. This individual also carried another pathogenic variant (ClinVar Variation ID: 99288) and a known risk variant (ClinVar Variation ID: 99390); however, the phase of these variants is unknown at this time. The p.Arg408Ter variant in ABCA4 has been previously reported in 13 unrelated individuals with autosomal recessive ABCA4-related retinopathy (PMID: 30771335, PMID: 14709597, PMID: 30060493, PMID: 33369172, PMID: 33301772, PMID: 32619608, PMID: 16103129, PMID: 23755871, PMID: 11846518) and segregated with disease in 2 affected relatives from one family (PMID: 16103129), but has been identified in 0.005% (1/19952) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs61748550). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 13 affected individuals (PMID: 30771335, PMID: 14709597, PMID: 30060493, PMID: 33369172, PMID: 33301772, PMID: 32619608, PMID: 16103129, PMID: 23755871, PMID: 11846518), 7 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 23755871, ClinVar Variation ID: 99224, 99283; PMID: 16103129, ClinVar Variation ID: 99084; PMID: 32619608, ClinVar Variation ID: 1065650; PMID: 33301772, ClinVar Variation ID: 99208; PMID: 33369172, ClinVar Variation ID: 854791; PMID: 30771335, ClinVar Variation ID: 7879), one was a compound heterozygote who carried a likely pathogenic variant with unknown phase (PMID: 11846518, ClinVar Variation ID: 99307), and 4 were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 32619608, ClinVar Variation ID: 7888, 99265; PMID: 33301772; PMID: 30060493, ClinVar Variation ID: 866940), which increases the likelihood that the p.Arg408Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 99035) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 408, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive ABCA4-related retinopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ABCA4-related retinopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003398695 SCV004122287 pathogenic Retinitis pigmentosa 2023-10-28 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.1222C>T (p.Arg408X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251456 control chromosomes. c.1222C>T has been reported in the literature in multiple individuals affected with Stargardt disease (e.g. Riveiro-Alvarez_2013) or other ABCA4-related retinopathy. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23755871). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Retina International RCV000085378 SCV000117515 not provided not provided no assertion provided not provided

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