rs61748526

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000350.3(ABCA4):​c.223T>G​(p.Cys75Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,084 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C75Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

13
5
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 9.16

Publications

10 publications found
Variant links:
Genes affected
ABCA4 (HGNC:34): (ATP binding cassette subfamily A member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is a retina-specific ABC transporter with N-retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essental molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile-onset macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. [provided by RefSeq, Sep 2019]
ABCA4 Gene-Disease associations (from GenCC):
  • ABCA4-related retinopathy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • cone-rod dystrophy 3
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • severe early-childhood-onset retinal dystrophy
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • retinitis pigmentosa 19
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • cone-rod dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • retinitis pigmentosa
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Stargardt disease
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000350.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-94111516-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2789051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 578 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: -0.65813 (below the threshold of 3.09). Trascript score misZ: 1.3628 (below the threshold of 3.09). GenCC associations: The gene is linked to cone-rod dystrophy 3, retinitis pigmentosa 19, ABCA4-related retinopathy, severe early-childhood-onset retinal dystrophy, cone-rod dystrophy, Stargardt disease, retinitis pigmentosa.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 1-94111517-A-C is Pathogenic according to our data. Variant chr1-94111517-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 99122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCA4NM_000350.3 linkc.223T>G p.Cys75Gly missense_variant Exon 3 of 50 ENST00000370225.4 NP_000341.2 P78363Q6AI28
ABCA4NM_001425324.1 linkc.223T>G p.Cys75Gly missense_variant Exon 3 of 49 NP_001412253.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCA4ENST00000370225.4 linkc.223T>G p.Cys75Gly missense_variant Exon 3 of 50 1 NM_000350.3 ENSP00000359245.3 P78363
ABCA4ENST00000649773.1 linkc.223T>G p.Cys75Gly missense_variant Exon 3 of 19 ENSP00000496882.1 A0A3B3IRV8

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152240
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461844
Hom.:
0
Cov.:
34
AF XY:
0.00000550
AC XY:
4
AN XY:
727226
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000899
AC:
10
AN:
1111972
Other (OTH)
AF:
0.00
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.460
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152240
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74382
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41448
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68048
Other (OTH)
AF:
0.000478
AC:
1
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1Other:1
Oct 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 75 of the ABCA4 protein (p.Cys75Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ABCA4-related conditions (PMID: 9973280, 23982839, 30093795). ClinVar contains an entry for this variant (Variation ID: 99122). 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. -

-
Retina International
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Severe early-childhood-onset retinal dystrophy Pathogenic:1
Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

Retinitis pigmentosa Pathogenic:1
Sep 24, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: ABCA4 c.223T>G (p.Cys75Gly) 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 was absent in 251414 control chromosomes. c.223T>G has been reported in the literature as a biallelic genotype in multiple individuals affected with features of Autosomal Recessive ABCA4-related disorders (example, Lewis_1999, Fujinami_2013, Salles_2018, Mena_2021, Webster_2001). These data indicate that the variant is very 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: 23982839, 9973280, 33841504, 30093795, 11328725). ClinVar contains an entry for this variant (Variation ID: 99122). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
D;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Pathogenic
3.0
M;.
PhyloP100
9.2
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-10
D;.
REVEL
Pathogenic
0.91
Sift
Uncertain
0.010
D;.
Sift4G
Uncertain
0.0060
D;.
Polyphen
0.91
P;.
Vest4
0.98
MutPred
0.91
Loss of stability (P = 0.0404);Loss of stability (P = 0.0404);
MVP
0.97
MPC
0.52
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.93
gMVP
0.97
Mutation Taster
=1/99
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs61748526; hg19: chr1-94577073; API