chr1-94029465-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1PM5PP3PP5_Very_StrongBP4
The NM_000350.3(ABCA4):c.4519G>A(p.Gly1507Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000327 in 1,561,378 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. G1507W) 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 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000162 AC: 28AN: 172758Hom.: 0 AF XY: 0.000164 AC XY: 15AN XY: 91606
GnomAD4 exome AF: 0.0000305 AC: 43AN: 1409082Hom.: 0 Cov.: 31 AF XY: 0.0000302 AC XY: 21AN XY: 696040
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74476
ClinVar
Submissions by phenotype
Severe early-childhood-onset retinal dystrophy Pathogenic:3
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Retinal dystrophy Pathogenic:2Uncertain:1
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ABCA4-related disorder Pathogenic:1
The ABCA4 c.4519G>A variant is predicted to result in the amino acid substitution p.Gly1507Arg. This variant has been reported in the compound heterozygous state in multiple individuals with ABCA4-related retinal disease (see for examples: Fujinami et al. 2013. PubMed ID: 23499370; Table S1, Ścieżyńska et al 2015. PubMed ID: 26593885; Table S1, Del Pozo-Valero et al. 2020. PubMed ID: 32619608; Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.10% of alleles in individuals of Latino descent in gnomAD. Given the evidence, we interpret this variant as pathogenic. -
not provided Pathogenic:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1507 of the ABCA4 protein (p.Gly1507Arg). This variant is present in population databases (rs568792949, gnomAD 0.1%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 23499370, 26593885, 27030965, 28041643). 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: 236115). 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. -
Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Pathogenic:1
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Stargardt disease Pathogenic:1
Variant summary: ABCA4 c.4519G>A (p.Gly1507Arg) results in a non-conservative amino acid change in 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 0.00016 in 172758 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Stargardt Disease (0.00016 vs 0.0014), allowing no conclusion about variant significance. c.4519G>A has been reported in the literature as a biallelic compound heterozygous genotype in individuals affected with Stargardt Disease (example, Fujinami_2013, Huckfeldt_2016, Lambertus_2016, Klufas_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28041643, 23499370, 27030965, 32307445, 28248825, 27699414, 26593885). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at