rs61750152
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000350.3(ABCA4):c.4577C>T(p.Thr1526Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,614,058 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1526A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000350.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.4577C>T | p.Thr1526Met | missense_variant | 31/50 | ENST00000370225.4 | |
ABCA4 | XM_047416704.1 | c.4355C>T | p.Thr1452Met | missense_variant | 30/49 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.4577C>T | p.Thr1526Met | missense_variant | 31/50 | 1 | NM_000350.3 | P1 | |
ABCA4 | ENST00000460514.1 | n.71C>T | non_coding_transcript_exon_variant | 2/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251482Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135914
GnomAD4 exome AF: 0.000127 AC: 185AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 74AN XY: 727244
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74352
ClinVar
Submissions by phenotype
Severe early-childhood-onset retinal dystrophy Pathogenic:4
Likely pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The ABCA4 c.4577C>T 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: PS3, PM2, PP3, PP5. Based on this evidence we have classified this variant as Likely Pathogenic. - |
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change is predicted to replace threonine with methionine at codon 1526 of the ABCA4 protein, p.(Thr1526Met). The threonine residue is moderately conserved (100 vertebrates, UCSC), and in the extracellular domain. There is a moderate physicochemical difference between threonine and methionine. The variant is present in a large population cohort at a frequency of 0.006%, which is consistent with recessive disease (rs61750152, 18/282,882 alleles, 0 homozygotes in gnomAD v2.1.1). Multiple Stargardt disease/ABCA4 retinopathy cases are compound heterozygous with a second pathogenic variant or homozygous (PMID: 9973280, 19074458, 28446513), and at least two affected segregations in a single family have been reported for the variant (PMID: 19074458). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PP1, PP3. - |
Pathogenic, no assertion criteria provided | research | Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana | - | - - |
not provided Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2023 | Published functional studies demonstrate reduced basal ATPase activity and almost absent retinal-stimulated activity (Sun et al., 2000); 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: 30653986, 34240658, 34758253, 32467599, 11527935, 21558428, 23918662, 11702214, 11726554, 23755871, 19265867, 21911583, 14517951, 9973280, 26551331, 23982839, 23143460, 30337596, 29925512, 28559085, 31456290, 32581362, 31618761, 32845068, 33301772, 32037395, 35119454, 35409265, 11017087, 19074458, 25082885) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 12, 2015 | - - |
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1526 of the ABCA4 protein (p.Thr1526Met). This variant is present in population databases (rs61750152, gnomAD 0.01%). This missense change has been observed in individuals with Stargardt disease or cone-rod dystrophy and Stargardt disease in at least one family and has been observed in unrelated individuals affected with Stargardt disease or cone-rod dystrophy (PMID: 9973280, 19074458). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99303). 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: 11017087). For these reasons, this variant has been classified as Pathogenic. - |
Retinitis pigmentosa 19 Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | Jan 23, 2015 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Age related macular degeneration 2 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 31, 2017 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 02, 2019 | - - |
Stargardt disease Pathogenic:1
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at