ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.3212C>T (p.Ser1071Leu)

gnomAD frequency: 0.00001  dbSNP: rs61750065
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085559 SCV000577305 pathogenic not provided 2023-07-11 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15192030, 23341817, 26720470, 31589614, 35156991, 33301772, 9973280, 29555955)
Labcorp Genetics (formerly Invitae), Labcorp RCV000085559 SCV001580409 pathogenic not provided 2024-12-19 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1071 of the ABCA4 protein (p.Ser1071Leu). This variant is present in population databases (rs61750065, gnomAD 0.006%). This missense change has been observed in individual(s) with ABCA4-related inherited retinal dystrophies (PMID: 9973280, 15192030, 26720470, 29555955; internal data). 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: 99208). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
DASA RCV002255094 SCV002526422 pathogenic ABCA4-related disorder 2022-06-10 criteria provided, single submitter clinical testing The c.3212C>T;p.(Ser1071Leu) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 99208; PMID: 29555955; PMID: 26720470) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (AAA_21; ABC_tran) - PM1. The variant is present at low allele frequencies population databases (rs61750065– gnomAD 0.0001314%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Ser1071Leu) was detected in trans with a Pathogenic variant (PMID: 26720470) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel RCV003324508 SCV004030376 pathogenic Cone-rod dystrophy 2023-07-24 criteria provided, single submitter research Clinical significance based on ACMG v2.0
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689455 SCV005185667 pathogenic Retinitis pigmentosa 2024-05-30 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.3212C>T (p.Ser1071Leu) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251470 control chromosomes. c.3212C>T has been reported in the literature in multiple individuals affected with ABCA4-related inherited retinal dystrophies (examples: Lewis_1999, Stenirri_2004, Muller_2015, Birtel_2018, Peter_2023). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29555955, 9973280, 26720470, 36909829, 15192030). ClinVar contains an entry for this variant (Variation ID: 99208). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005025155 SCV005657433 pathogenic Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 2024-06-13 criteria provided, single submitter clinical testing
Retina International RCV000085559 SCV000117696 not provided not provided no assertion provided not provided
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV004815102 SCV005072203 pathogenic Retinal dystrophy 2007-01-01 no assertion criteria provided clinical testing

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