1-94019641-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM5PP2PP3_ModeratePP5

The NM_000350.3(ABCA4):​c.5137C>A​(p.Gln1713Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,192 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1713R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

12
6
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 9.93

Publications

2 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: Likely_pathogenic. The variant received 8 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000350.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-94019640-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1212473.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, 0.936
PP5
Variant 1-94019641-G-T is Pathogenic according to our data. Variant chr1-94019641-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 236124.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCA4NM_000350.3 linkc.5137C>A p.Gln1713Lys missense_variant Exon 36 of 50 ENST00000370225.4 NP_000341.2 P78363Q6AI28
ABCA4NM_001425324.1 linkc.4915C>A p.Gln1639Lys missense_variant Exon 35 of 49 NP_001412253.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCA4ENST00000370225.4 linkc.5137C>A p.Gln1713Lys missense_variant Exon 36 of 50 1 NM_000350.3 ENSP00000359245.3 P78363
ABCA4ENST00000460514.1 linkn.631C>A non_coding_transcript_exon_variant Exon 7 of 7 5
ABCA4ENST00000470771.1 linkn.247C>A non_coding_transcript_exon_variant Exon 2 of 2 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000121
AC:
3
AN:
247790
AF XY:
0.0000224
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000268
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1460192
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726126
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33462
American (AMR)
AF:
0.00
AC:
0
AN:
44486
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26080
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39668
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85816
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53324
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.00000720
AC:
8
AN:
1111248
Other (OTH)
AF:
0.00
AC:
0
AN:
60344
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
1
1
2
2
3
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
Cov.:
32
Alfa
AF:
0.0000312
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy Pathogenic:1
Jan 01, 2016
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Pathogenic:1
May 26, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gln1713 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21911583, 29178665). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has been observed in individual(s) with Stargardt disease (PMID: 28118664, 29925512, Invitae). ClinVar contains an entry for this variant (Variation ID: 236124). This variant is present in population databases (rs374343397, ExAC 0.008%). This sequence change replaces glutamine with lysine at codon 1713 of the ABCA4 protein (p.Gln1713Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. -

Retinal dystrophy Pathogenic:1
Jan 01, 2010
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Retinitis pigmentosa Pathogenic:1
Feb 10, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: ABCA4 c.5137C>A (p.Gln1713Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 247790 control chromosomes (gnomAD). c.5137C>A has been reported in the literature in individuals affected with Stargardt disease or inherited retinal degeneration (Schulz_2017, Fujinami_2019, Ramkumar_2019). 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: 29925512, 31964843, 28005406, 28118664). ClinVar contains an entry for this variant (Variation ID: 236124). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

ABCA4-related retinopathy Uncertain:1
Feb 01, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Uncertain
0.79
D
MutationAssessor
Pathogenic
3.5
.;M
PhyloP100
9.9
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.5
.;D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0060
.;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
.;D
Vest4
0.99
MVP
0.99
MPC
0.42
ClinPred
0.97
D
GERP RS
5.4
Varity_R
0.94
gMVP
0.99
Mutation Taster
=2/98
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: rs374343397; hg19: chr1-94485197; API