rs61749451
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM5PP2PP3_StrongPP5_Moderate
The NM_000350.3(ABCA4):c.2915C>T(p.Thr972Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,002 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. T972N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000350.3 missense
Scores
Clinical Significance
Conservation
Publications
- ABCA4-related retinopathyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- cone-rod dystrophy 3Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- severe early-childhood-onset retinal dystrophyInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
- retinitis pigmentosa 19Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- cone-rod dystrophyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- retinitis pigmentosaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Stargardt diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.2915C>T | p.Thr972Ile | missense_variant | Exon 19 of 50 | 1 | NM_000350.3 | ENSP00000359245.3 | ||
ABCA4 | ENST00000649773.1 | c.2693C>T | p.Thr898Ile | missense_variant | Exon 18 of 19 | ENSP00000496882.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152204Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000199 AC: 5AN: 251226 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461798Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727210 show subpopulations
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74368 show subpopulations
ClinVar
Submissions by phenotype
not provided Pathogenic:1
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 972 of the ABCA4 protein (p.Thr972Ile). This variant is present in population databases (rs61749451, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ABCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1472288). 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.Thr972 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28041643, 28559085, 29925512). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at