ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1906C>T (p.Gln636Ter)

gnomAD frequency: 0.00002  dbSNP: rs145961131
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256006 SCV000321340 pathogenic not provided 2019-06-28 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: 29925512, 24020726, 29884405, 22968130, 21911583, 22863181, 28559085, 30204727)
Labcorp Genetics (formerly Invitae), Labcorp RCV000256006 SCV001224888 pathogenic not provided 2024-11-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln636*) 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 (rs145961131, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with ABCA4-related disorders including Stargardt disease and retinitis pigmentosa (PMID: 21911583, 22968130, 28041643). ClinVar contains an entry for this variant (Variation ID: 265012). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075471 SCV001241094 pathogenic Retinal dystrophy 2018-10-12 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000504776 SCV002556480 pathogenic Severe early-childhood-onset retinal dystrophy 2021-11-04 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002518745 SCV003761280 pathogenic Retinitis pigmentosa 19 2023-01-25 criteria provided, single submitter curation The heterozygous p.Gln636Ter variant in ABCA4 was identified by our study, in the compound heterozygous state with another pathogenic variant (ClinVar Variation ID: 99478). This individual also carried another pathogenic variant (ClinVar Variation ID: 99478); however, the phase of these variants is unknown at this time. The p.Gln636Ter variant in ABCA4 has been previously reported in 8 unrelated individuals with autosomal recessive ABCA4-related retinopathy (PMID: 24020726, PMID: 29884405, PMID: 22863181, PMID: 28559085, PMID: 30204727, PMID: 28041643, PMID: 22968130, PMID: 21911583), but has been identified in 0.004% (5/113446) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs145961131). 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 8 previously reported individuals (PMID: 24020726, PMID: 29884405, PMID: 22863181, PMID: 28559085, PMID: 30204727, PMID: 28041643, PMID: 22968130, PMID: 21911583), 1 was a homozygote (PMID: 21911583), 6 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 24020726, ClinVar Variation ID: 92870; PMID: 29884405, ClinVar Variation ID: 7879; PMID: 28559085, ClinVar Variation ID: 7879; PMID: 30204727, ClinVar Variation ID: 99390; PMID: 28041643, ClinVar Variation ID: 30218; PMID: 22968130, ClinVar Variation ID: 99505) and 1 was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 22863181, ClinVar Variation ID: 7888), which increases the likelihood that the p.Gln636Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 265012) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 636, 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).
Fulgent Genetics, Fulgent Genetics RCV005025404 SCV005661416 pathogenic Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 2024-06-07 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504776 SCV000598944 pathogenic Severe early-childhood-onset retinal dystrophy 2015-01-01 no assertion criteria provided research

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