ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4222T>C (p.Trp1408Arg) (rs61750135)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408501 SCV000281881 pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085613 SCV000321350 pathogenic not provided 2018-10-04 criteria provided, single submitter clinical testing The W1408R pathogenic variant in the ABCA4 gene has been reported previously in autosomal recessive Stargardt disease in affected individuals when in trans with another pathogenic variant (Lewis et al., 1999). The W1408R variant has been reported on the same allele (in cis) with the R1640W variant in families with Stargardt disease, and in a family presenting with both Stargardt disease and retinitis pigmentosa, when in trans with another pathogenic variant (Valverde et al, 2006; Shroyer et al, 2001). Shroyer et al. (2001) showed very little protein from cells transfected with the W1408R and R1640W variants in cis; however, proteins bearing only the W1408R or the R1640W variants appear to have mild or moderate defects in expression or stability. Sun et al. (2000) showed the W1408R variant had reduced basal ATPase activity compared to wild-type. The W1408R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W1408R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret W1408R as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000085613 SCV000339313 other not provided 2017-08-31 criteria provided, single submitter clinical testing
Invitae RCV000085613 SCV001230608 pathogenic not provided 2020-06-24 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 1408 of the ABCA4 protein (p.Trp1408Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs61750135, ExAC 0.002%). This variant has been observed in individual(s) with ABCA4-related conditions. While this variant is commonly found in cis with the variant p.Arg1640Trp, it has also been observed without p.Arg1640Trp in affected individuals (PMID: 9973280, 29925512). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from p.Arg1640Trp (PMID: 28559085). ClinVar contains an entry for this variant (Variation ID: 99260). This variant has been reported to affect ABCA4 protein function (PMID: 11687513, 11017087). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000210333 SCV001239107 pathogenic Retinal dystrophy 2019-06-16 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV000408501 SCV001573565 pathogenic Stargardt disease 1 2021-04-08 criteria provided, single submitter research The ABCA4 c.4222T>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PM1, PM3-S. Based on this evidence we have classified this variant as Pathogenic.
Retina International RCV000085613 SCV000117752 not provided not provided no assertion provided not provided
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000210333 SCV000259104 pathogenic Retinal dystrophy 2015-01-30 no assertion criteria provided clinical testing

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