rs61750147
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The ENST00000370225.4(ABCA4):c.4463G>T(p.Cys1488Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,608,892 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. C1488R) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.4463G>T | p.Cys1488Phe | missense_variant | 30/50 | ENST00000370225.4 | NP_000341.2 | |
ABCA4 | XM_047416704.1 | c.4241G>T | p.Cys1414Phe | missense_variant | 29/49 | XP_047272660.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.4463G>T | p.Cys1488Phe | missense_variant | 30/50 | 1 | NM_000350.3 | ENSP00000359245 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000822 AC: 2AN: 243254Hom.: 0 AF XY: 0.0000153 AC XY: 2AN XY: 131124
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1456670Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11AN XY: 723998
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74368
ClinVar
Submissions by phenotype
Severe early-childhood-onset retinal dystrophy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change is predicted to replace cysteine with phenylalanine at codon 1488 of the ABCA4 protein, p.(Cys1488Phe). The cysteine residue is highly conserved (100 vertebrates, UCSC), and is predicted to form a disulphide bond. There is a large physicochemical difference between cysteine and phenylalanine. The variant is present in a large population cohort at a frequency of 0.0008%, which is consistent with recessive disease (rs61750147, 2/243,254 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in at least one Stargardt disease case with another pathogenic variant (PMID: 11673412). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Two different missense changes at the same position (p.Cys1488Tyr, p.Cys1488Arg) determined to be likely pathogenic/pathogenic have been seen before (ClinVar IDs: 99284, 99285). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PM5, PM3_Supporting, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 09, 2024 | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease (MIM #248200), cone-rod dystrophy 3 (MIM #6041163), fundus flavimaculatus (MIM #248200), early-onset severe Retinal dystrophy (MIM #248200) and retinitis pigmentosa 19 (MIM #601718). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (29 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (highest allele count: 15 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located at an annotated cysteine residue that is involved in a disulphide bond (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case has very strong previous evidence for pathogenicity. p.(Cys1488Arg) and p.(Cys1488Tyr) have been identified in multiple individuals with Stargardt disease (ClinVar; PMID: 22449572, 23769331, 29854428, 31766579, 30820146). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in at least five individuals with Stargardt disease (Clinvar; PMID: 11328725). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 1488 of the ABCA4 protein (p.Cys1488Phe). This variant is present in population databases (rs61750147, gnomAD 0.002%). This missense change has been observed in individuals with Stargardt disease (PMID: 20647261; Invitae). ClinVar contains an entry for this variant (Variation ID: 99286). 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.Cys1488 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22449572, 28559085, 29555955, 29925512). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at