rs61751402
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong
The NM_000350.3(ABCA4):โc.4469G>Aโ(p.Cys1490Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,606,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1490S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000350.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.4469G>A | p.Cys1490Tyr | missense_variant | 30/50 | ENST00000370225.4 | |
ABCA4 | XM_047416704.1 | c.4247G>A | p.Cys1416Tyr | missense_variant | 29/49 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.4469G>A | p.Cys1490Tyr | missense_variant | 30/50 | 1 | NM_000350.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000626 AC: 15AN: 239526Hom.: 0 AF XY: 0.0000465 AC XY: 6AN XY: 129058
GnomAD4 exome AF: 0.000166 AC: 242AN: 1454130Hom.: 0 Cov.: 31 AF XY: 0.000147 AC XY: 106AN XY: 722500
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74364
ClinVar
Submissions by phenotype
not provided Pathogenic:8Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tรผbingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2020 | - - |
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 31, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1490 of the ABCA4 protein (p.Cys1490Tyr). This variant is present in population databases (rs61751402, gnomAD 0.01%). This missense change has been observed in individual(s) with Stargardt disease and retinitis pigmentosa (PMID: 23695285, 24713488, 25082885, 25472526, 28041643). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of South African ancestry (PMID: 23695285, 24713488, 25082885, 25472526, 28041643). ClinVar contains an entry for this variant (Variation ID: 99288). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 16103129). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2022 | Published functional studies demonstrate a damaging effect with reduced basal and retinal ATPase activities relative to wild-type as well as impaired protein folding and localization (Sun et al., 2000; Wiszniewski et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24713488, 25472526, 9973280, 31429209, 32531858, 33706644, 34758253, 35456422, 23695285, 25082885, 25097241, 26261413, 16103129, 28118664, 29310964, 15161829, 16917483, 30204727, 29925512, 32467599, 31980526, 32581362, 31589614, 32619608, 11017087) - |
Severe early-childhood-onset retinal dystrophy Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing;in vitro | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The ABCA4 c.4469G>A 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, PM3-S, PS3. Based on this evidence we have classified this variant as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Retinal dystrophy Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | Jan 30, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 16, 2019 | - - |
ABCA4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 14, 2018 | Across a selection of the available literature, the ABCA4 c.4469G>A (p.Cys1490Tyr) missense variant has been identified in one individual with cone rod dystrophy in a compound heterozygous state and in eight individuals with Stargardt disease, including in one in a homozygous state, in six in a compound heterozygous state, and in one in a heterozygous state. The individual who was heterozygous for the p.Cys1490Tyr variant also carried two additional variants for which zygosity was not determined (Lewis et al. 1999; Stenirri et al. 2004; Wiszniewski et al. 2005). The p.Cys1490Tyr variant has not been seen in the literature in association with autosomal recessive retinitis pigmentosa or autosomal dominant macular degeneration. The p.Cys1490Tyr variant was absent from 220 controls and is reported at a frequency of 0.00038 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression of the p.Cys1490Tyr variant protein in HEK293 cells revealed protein levels comparable to wild type but somewhat reduced basal ATPase activity (Sun et al. 2000). Expression in COS7 cells revealed that variant protein resulted in the rate of ATP hydrolysis being decreased to 21.4% of wild type. Expression in transgenic frogs demonstrated that the p.Cys1490Tyr variant protein was mislocalized (Wiszniewski et al. 2005). Based on the collective evidence, the p.Cys1490Tyr variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Macular dystrophy Pathogenic:1
Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 16, 2021 | ACMG categories: PS3,PS4,PM3,PP1,PP4,PP5 - |
Retinitis pigmentosa 19 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at