rs61751402

Positions:

chr1-94029515-C-T

Variant summary

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

The NM_000350.3(ABCA4):c.4469G>A(p.Cys1490Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,606,364 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. C1490S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17O:2

Conservation

PhyloP100: 7.77

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 hotspot region, there are 2 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 chr1-94029516-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 866086.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-94029515-C-T is Pathogenic according to our data. Variant chr1-94029515-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 99288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94029515-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94029515-C-T is described in Lovd as [Pathogenic]. Variant chr1-94029515-C-T is described in Lovd as [Likely_benign]. Variant chr1-94029515-C-T is described in Lovd as [Pathogenic]. Variant chr1-94029515-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.4469G>A	p.Cys1490Tyr	missense_variant	30/50	ENST00000370225.4
ABCA4	XM_047416704.1 linkuse as main transcript	c.4247G>A	p.Cys1416Tyr	missense_variant	29/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.4469G>A	p.Cys1490Tyr	missense_variant	30/50	1	NM_000350.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000626

AC:

AN:

239526

Hom.:

AF XY:

0.0000465

AC XY:

AN XY:

129058

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000139

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000166

AC:

242

AN:

1454130

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

106

AN XY:

722500

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000209

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000875

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1490 of the ABCA4 protein (p.Cys1490Tyr). This variant is present in population databases (rs61751402, gnomAD 0.01%). This missense change has been observed in individual(s) with Stargardt disease and retinitis pigmentosa (PMID: 23695285, 24713488, 25082885, 25472526, 28041643). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of South African ancestry (PMID: 23695285, 24713488, 25082885, 25472526, 28041643). ClinVar contains an entry for this variant (Variation ID: 99288). 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: 16103129). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2022	Published functional studies demonstrate a damaging effect with reduced basal and retinal ATPase activities relative to wild-type as well as impaired protein folding and localization (Sun et al., 2000; Wiszniewski et al., 2005); 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: 24713488, 25472526, 9973280, 31429209, 32531858, 33706644, 34758253, 35456422, 23695285, 25082885, 25097241, 26261413, 16103129, 28118664, 29310964, 15161829, 16917483, 30204727, 29925512, 32467599, 31980526, 32581362, 31589614, 32619608, 11017087) -

Severe early-childhood-onset retinal dystrophy

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing;in vitro	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2016	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The ABCA4 c.4469G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3-S, PS3. Based on this evidence we have classified this variant as Pathogenic. -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Retinal dystrophy

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Jan 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 16, 2019	- -

ABCA4-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 14, 2018

Across a selection of the available literature, the ABCA4 c.4469G>A (p.Cys1490Tyr) missense variant has been identified in one individual with cone rod dystrophy in a compound heterozygous state and in eight individuals with Stargardt disease, including in one in a homozygous state, in six in a compound heterozygous state, and in one in a heterozygous state. The individual who was heterozygous for the p.Cys1490Tyr variant also carried two additional variants for which zygosity was not determined (Lewis et al. 1999; Stenirri et al. 2004; Wiszniewski et al. 2005). The p.Cys1490Tyr variant has not been seen in the literature in association with autosomal recessive retinitis pigmentosa or autosomal dominant macular degeneration. The p.Cys1490Tyr variant was absent from 220 controls and is reported at a frequency of 0.00038 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression of the p.Cys1490Tyr variant protein in HEK293 cells revealed protein levels comparable to wild type but somewhat reduced basal ATPase activity (Sun et al. 2000). Expression in COS7 cells revealed that variant protein resulted in the rate of ATP hydrolysis being decreased to 21.4% of wild type. Expression in transgenic frogs demonstrated that the p.Cys1490Tyr variant protein was mislocalized (Wiszniewski et al. 2005). Based on the collective evidence, the p.Cys1490Tyr 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. -

Macular dystrophy

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 16, 2021

ACMG categories: PS3,PS4,PM3,PP1,PP4,PP5 -

Retinitis pigmentosa 19

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomics England Pilot Project, Genomics England

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.76

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.93

MVP

0.99

MPC

0.60

ClinPred

0.95

GERP RS

5.2

Varity_R

0.95

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.80

Position offset: 3

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