chr1-94031110-G-A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PP2PP3_ModeratePP5_Very_Strong

The NM_000350.3(ABCA4):​c.4139C>T​(p.Pro1380Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,613,962 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P1380P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

12
6
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:2

Conservation

PhyloP100: 9.89
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000350.3
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 severe early-childhood-onset retinal dystrophy, ABCA4-related retinopathy, cone-rod dystrophy 3, Stargardt disease, retinitis pigmentosa 19, cone-rod dystrophy, retinitis pigmentosa.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.888
PP5
Variant 1-94031110-G-A is Pathogenic according to our data. Variant chr1-94031110-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94031110-G-A is described in Lovd as [Pathogenic]. Variant chr1-94031110-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94031110-G-A is described in Lovd as [Likely_benign]. Variant chr1-94031110-G-A is described in Lovd as [Pathogenic]. Variant chr1-94031110-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCA4NM_000350.3 linkc.4139C>T p.Pro1380Leu missense_variant Exon 28 of 50 ENST00000370225.4 NP_000341.2 P78363Q6AI28
ABCA4NM_001425324.1 linkc.3917C>T p.Pro1306Leu missense_variant Exon 27 of 49 NP_001412253.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCA4ENST00000370225.4 linkc.4139C>T p.Pro1380Leu missense_variant Exon 28 of 50 1 NM_000350.3 ENSP00000359245.3 P78363

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000426
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000239
AC:
60
AN:
251084
AF XY:
0.000206
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00239
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000293
AC:
429
AN:
1461766
Hom.:
0
Cov.:
32
AF XY:
0.000285
AC XY:
207
AN XY:
727156
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33478
American (AMR)
AF:
0.0000447
AC:
2
AN:
44706
Ashkenazi Jewish (ASJ)
AF:
0.00180
AC:
47
AN:
26134
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39698
South Asian (SAS)
AF:
0.000220
AC:
19
AN:
86214
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.000299
AC:
332
AN:
1111960
Other (OTH)
AF:
0.000431
AC:
26
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
27
54
80
107
134
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<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:
0.000243
AC:
37
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.000202
AC XY:
15
AN XY:
74358
show subpopulations
African (AFR)
AF:
0.0000724
AC:
3
AN:
41446
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00115
AC:
4
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000426
AC:
29
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.000266
Hom.:
0
Bravo
AF:
0.000204
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000198
AC:
24
EpiCase
AF:
0.000218
EpiControl
AF:
0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:23Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:8Other:1
Jul 01, 2019
CeGaT Center for Human Genetics Tuebingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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

- -

Jun 23, 2021
Revvity Omics, Revvity
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 09, 2013
Eurofins Ntd Llc (ga)
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 12, 2023
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26766544, 28559085, 29925512, 31429209, 32531858, 33706644, 34315337, 35456422, 33369172, 32037395, 25283059, 15579991, 9973280, 25087612, 11527935, 28341476, 28041643, 19074458, 10396622, 16682602, 30634128, 30204727, 30718709, 11017087, 32467599, 31456290, 32581362, 33375396, 34426522, 31573552, 31589614, 32619608, 27030965, 28947085, 35119454) -

-
Clinical Genetics, Academic Medical Center
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 31, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1380 of the ABCA4 protein (p.Pro1380Leu). This variant is present in population databases (rs61750130, gnomAD 0.2%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 9973280, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7904). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic. -

Severe early-childhood-onset retinal dystrophy Pathogenic:5
Jan 30, 2021
Institute of Medical Molecular Genetics, University of Zurich
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 01, 2006
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

-
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

Sep 25, 2021
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

Stargardt disease Pathogenic:3
Jul 24, 2023
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

Clinical significance based on ACMG v2.0 -

Jun 23, 2019
Sharon lab, Hadassah-Hebrew University Medical Center
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

Apr 01, 2018
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

ABCA4-related disorder Pathogenic:2
Sep 13, 2024
PreventionGenetics, part of Exact Sciences
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

The ABCA4 c.4139C>T variant is predicted to result in the amino acid substitution p.Pro1380Leu. This variant has been reported many times in the homozygous and compound heterozygous states in individuals with ABCA4-related retinal disease (see for examples: Lewis et al. 1999. PubMed ID: 9973280; Oh et al. 2004. PubMed ID: 15579991; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858; Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.23% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, indicating it is relatively common in this population. This variant is interpreted as pathogenic. -

Aug 21, 2018
Illumina Laboratory Services, Illumina
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The ABCA4 c.4139C>T (p.Pro1380Leu) missense variant has been reported in at least ten studies in which it is found in at least 38 individuals with either Stargardt disease (STGD), cone-rod dystrophy or age related macular degeneration including in five individuals in a homozygous state, at least 29 in a compound heterozygous state, and four individuals in a heterozygou state (Shroyer et al. 1999; Lewis et al. 1999; Shroyer et al. 2001; Briggs et al. 2001; Oh et al. 2004; Fingert et al. 2006; Hwang et al. 2009; Cideciyan et al. 2009; Chacón-Camacho et al. 2013; Duncker et al. 2015). The p.Pro1380Leu variant has been shown to segregate with STGD disease in at least three families (Lewis et al. 1999; Shroyer et al. 2001; Cideciyan et al. 2009). The variant has not been reported in association with retinitis pigmentosa. The p.Pro1380Leu variant was absent from at least 895 controls and is reported at a frequency of 0.001973 in the Ashkenazi Jewish population of the Genome Aggregation Database. In vitro analysis in HEK-293 cells demonstrated that the p.Pro1380Leu variant resulted in reduced expression of the protein and defective ATP binding (Sun et al. 2000). Based on the collective evidence, the p.Pro1380Leu variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Retinal dystrophy Pathogenic:2
Jan 01, 2022
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 14, 2019
Blueprint Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mandibulofacial dysostosis with mental deficiency Pathogenic:1
Jul 24, 2015
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant has been observed, either as homozygous (Hwang JC et al., 2009) or compound heterozygous (Lewis RA et al., 1999) in individuals who have been diagnosed with Stargardt disease. It co-segregates with disease and was found in trans with the known pathogenic variant, G1961E (Duncker T et al., 2015). In the protein, it is present in the helical transmembrane domain 7 and is close to the nucleotide binding domain-1. Studies in HEK 293 cells showed that, compared with wild-type, the protein yield and ATP-binding capacity of this variant was reduced (Sun H et al., 2000). Finally, multiple computational algorithms predict this variant to be deleterious and its frequency in the population databases (1000 Genomes, Exome Sequencing Project [ESP] and ExAC) is either absent or very low. Therefore, this variant meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. -

Cone-rod dystrophy 3 Pathogenic:1
May 25, 2020
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. 0108 - This gene is known to be associated with both recessive and dominant disease. 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine (exon 28). 0304 - Variant is present in gnomAD <0.01 for recessive indication (66 heterozygotes, 0 homozygotes) 0501 - Missense variant consistently predicted to be damaging by in-silico tools or highly conserved with a major amino acid change. 0604 - Variant is not located in an established domain, motif or hotspot. 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously described as pathogenic in multiple individuals (PMID: ClinVar, 11726554, 28947085) 1002 - Moderate functional evidence supporting abnormal protein function. Functional analysis demonstrated that the variant resulted in reduced expression of the protein and defective ATP binding (PMID: 11017087) 1205 - Variant is maternally inherited. -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Pathogenic:1
Jun 14, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

MACULAR DEGENERATION, AGE-RELATED, 2, SUSCEPTIBILITY TO Other:1
May 01, 2006
OMIM
Significance:risk factor
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.53
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
D;D
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
.;M
PhyloP100
9.9
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-8.7
.;D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.013
.;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
0.99
.;D
Vest4
0.97
MVP
0.99
MPC
0.33
ClinPred
0.82
D
GERP RS
5.0
Varity_R
0.35
gMVP
0.90
Mutation Taster
=11/89
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs61750130; hg19: chr1-94496666; API