rs1801269

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong

The NM_000350.3(ABCA4):c.3386G>T(p.Arg1129Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000102 in 1,614,062 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. R1129C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 6.16

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a domain ABC transporter 1 (size 231) in uniprot entity ABCA4_HUMAN there are 317 pathogenic changes around while only 11 benign (97%) in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94041346-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.789

PP5

Variant 1-94041345-C-A is Pathogenic according to our data. Variant chr1-94041345-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94041345-C-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94041345-C-A is described in Lovd as [Pathogenic]. Variant chr1-94041345-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.3386G>T	p.Arg1129Leu	missense_variant	23/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1 linkuse as main transcript	c.3164G>T	p.Arg1055Leu	missense_variant	22/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.3386G>T	p.Arg1129Leu	missense_variant	23/50	1	NM_000350.3	ENSP00000359245	P1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

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:

0.000118

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000306

AC:

AN:

251440

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.0000869

AC:

127

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000243

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.0000927

Hom.:

Bravo

AF:

0.000329

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2022	Reported as a common pathogenic variant among individuals of Spanish background (Riveiro-Alvarez et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28771251, 29114839, 27032803, 30337596, 30093795, 32483926, 32845050, 32036094, 25698705, 17277736, 9295268, 29555955, 28118664, 19074458, 16917483, 30156925, 32141364, 32619608, 31589614, 34327195, 34426522, 33090715, 33302505, 11017087, 23755871, 29925512) -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1129 of the ABCA4 protein (p.Arg1129Leu). This variant is present in population databases (rs1801269, gnomAD 0.2%). This missense change has been observed in individual(s) with Stargardt disease or cone-rod dystrophy (PMID: 19074458, 23755871, 27032803, 29114839). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99224). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic. -

Age related macular degeneration 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 27, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM5,PP2,PP3,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Severe early-childhood-onset retinal dystrophy

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2016	- -

ABCA4-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2024

The ABCA4 c.3386G>T variant is predicted to result in the amino acid substitution p.Arg1129Leu. This variant has been reported to be causative for autosomal recessive retinal disorders and is a prevalent pathogenic variant in Mexican Stargardt disease patients (Bravo-Gil et al. 2016. PubMed ID: 27032803; Riveiro-Alvarez et al. 2007. PubMed ID: 17277736; Riveiro-Alvarez et al. 2013. PubMed ID: 23755871). This variant is reported in 0.17% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 03, 2022

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.98

MVP

0.88

MPC

0.44

ClinPred

0.45

GERP RS

4.6

Varity_R

0.84

gMVP

0.93

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over