rs62645958
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM5PP5_Very_StrongBP4
The ENST00000370225.4(ABCA4):c.71G>A(p.Arg24His) variant causes a missense change. The variant allele was found at a frequency of 0.0000669 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R24C) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000370225.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.71G>A | p.Arg24His | missense_variant | 2/50 | ENST00000370225.4 | NP_000341.2 | |
ABCA4 | XM_047416704.1 | c.71G>A | p.Arg24His | missense_variant | 2/49 | XP_047272660.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.71G>A | p.Arg24His | missense_variant | 2/50 | 1 | NM_000350.3 | ENSP00000359245 | P1 | |
ABCA4 | ENST00000649773.1 | c.71G>A | p.Arg24His | missense_variant | 2/19 | ENSP00000496882 |
Frequencies
GnomAD3 genomes AF: 0.0000855 AC: 13AN: 152022Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000179 AC: 45AN: 250860Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135682
GnomAD4 exome AF: 0.0000650 AC: 95AN: 1461704Hom.: 0 Cov.: 34 AF XY: 0.0000646 AC XY: 47AN XY: 727154
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74362
ClinVar
Submissions by phenotype
not provided Pathogenic:3Other:1
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 24 of the ABCA4 protein (p.Arg24His). This variant is present in population databases (rs62645958, gnomAD 0.1%). This missense change has been observed in individuals with retinopathy (PMID: 9973280, 27820952, 31015497). ClinVar contains an entry for this variant (Variation ID: 99498). 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%. This variant disrupts the p.Arg24 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15494742, 28559085, 29162642, 30093795). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | Retina International | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 30, 2020 | - - |
Retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 23, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2016 | - - |
ABCA4-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 31, 2017 | Across a selection of literature, the ABCA4 c.71G>A (p.Arg24His) missense variant has been reported in a compound heterozygous state in five individuals with Stargardt disease (STGD) as well as in a heterozygous state in one individual (also with STGD) where a second variant was not identified (Lewis et al., 1999; Fujinami et al., 2013; Chacón-Camacho et al., 2013). Four of the compound heterozygous individuals belong to the same family and demonstrated segregation of the disease phenotype with the p.Arg24His variant. The p.Arg24His variant was absent from 440 control chromosomes and is reported at a frequency of 0.002091 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg24His variant is classified as likely pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PP3_Moderate+PM3_Strong+PP1_Moderate+PP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at