rs61749410

Positions:

chr1-94062709-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate

The NM_000350.3(ABCA4):c.1805G>A(p.Arg602Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000465 in 1,613,988 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. R602W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.98

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:

ABCA4 (HGNC:):

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94062710-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.1805G>A	p.Arg602Gln	missense_variant	13/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.1805G>A	p.Arg602Gln	missense_variant	13/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.1805G>A	p.Arg602Gln	missense_variant	13/50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000649773.1 linkuse as main transcript	c.1805G>A	p.Arg602Gln	missense_variant	13/19			ENSP00000496882.1		A0A3B3IRV8

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250860

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135588

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000451

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 602 of the ABCA4 protein (p.Arg602Gln). This variant is present in population databases (rs61749410, gnomAD 0.008%). This missense change has been observed in individuals with retinal disease (PMID: 20696155, 22449572, 23982839, 25472526, 25910913). ClinVar contains an entry for this variant (Variation ID: 99085). 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%. This variant disrupts the p.Arg602 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16103129, 23755871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

ABCA4-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Across a selection of the available literature, the ABCA4 c.1805G>A (p.Arg602Gln) missense variant has been reported in a total of seven individuals with Stargardt disease including in one in a homozygous state, four in a compound heterozygous state, and two in a heterozygous state in whom a second variant has not been identified (Briggs et al. 2001; Webster et al. 2001; Ernest et al. 2009; Burke et al. 2010; Zernant et al. 2011; Fujinami et al. 2013; Gemenetzi et al. 2013). The authors suggested the presence of the variant in a heterozygous state in patients may be attributed to the large size and allelic heterogeneity of the ABCA4 gene. Overlapping phenotypes with other ABCA4 associated diseases such as cone-rod dystrophy, dominant forms of macular deneration, and retinitis pigmentosa may also complicate the identification of disease-causing ABCA4 variants. The p.Arg602Gln variant was absent from at least 96 controls and is reported at a frequency of 0.00023 in the African American population of the Exome Sequencing Project, but this is based on one allele in an area of good coverage so the variant is presumed to be rare. The variant is significantly over-represented in the affected population, and is likely contributing to disease. Based on the evidence, the p.Arg602Gln variant is classified as likely 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:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.7

D;.

REVEL

Pathogenic

0.84

Sift

Benign

0.050

D;.

Sift4G

Benign

0.067

T;.

Polyphen

0.90

P;.

Vest4

0.78

MVP

0.96

MPC

0.50

ClinPred

0.76

GERP RS

4.0

Varity_R

0.36

gMVP

0.88

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