rs62642574

chr1-94024994-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_000350.3(ABCA4):c.4594G>A(p.Asp1532Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000458 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. D1532E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 7.76

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94024992-G-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852
• PP5: Variant 1-94024994-C-T is Pathogenic according to our data. Variant chr1-94024994-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94024994-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94024994-C-T is described in Lovd as [Pathogenic]. Variant chr1-94024994-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.4594G>A	p.Asp1532Asn	missense_variant	31/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.4372G>A	p.Asp1458Asn	missense_variant	30/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.4594G>A	p.Asp1532Asn	missense_variant	31/50	1	NM_000350.3	P1
ABCA4	ENST00000460514.1	n.88G>A		non_coding_transcript_exon_variant	2/7	5

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251478 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1532 of the ABCA4 protein (p.Asp1532Asn). This variant is present in population databases (rs62642574, gnomAD 0.2%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 9973280, 11726554, 19217903, 22589445, 24409374, 29925512; Invitae). 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: 99304). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 24, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2023	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: 28118664, 9973280, 19217903, 22589445, 30055151, 29925512, 28559085, 29343940, 32013026, 31456290, 31589614, 32037395, 24409374, 33505770, 11726554) -
not provided, no classification provided	literature only	Retina International	-	- -

Severe early-childhood-onset retinal dystrophy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 01, 2023	Criteria applied: PS4,PM2_SUP,PP3 -

ABCA4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2023

The ABCA4 c.4594G>A variant is predicted to result in the amino acid substitution p.Asp1532Asn. This variant has previously been reported to be causative for autosomal recessive Stargardt disease (see for example - Gomes et al. 2009. PubMed ID: 19324865; Lewis et al. 1999. PubMed ID: 9973280; Schulz et al. 2017. PubMed ID: 28118664). This variant is reported in 0.21% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94490550-C-T). This variant is interpreted as pathogenic. -

maculopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 27, 2019

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 30, 2023

Variant summary: ABCA4 c.4594G>A (p.Asp1532Asn) 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 0.00011 in 251478 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.00011 vs 0.0014), allowing no conclusion about variant significance. c.4594G>A has been reported in the literature in multiple individuals affected with Stargardt disease and bull's eye maculopathy (examples: Lewis_1999, Shroyer_2001, Cella_2009, Giani_2012, Verdina_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11726554, 19217903 , 22589445, 24409374 , 9973280 ). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Age-related macular degeneration;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 02-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.79	T
Sift4G	Uncertain	0.045	D;D
Polyphen		0.99	.;D
Vest4		0.92
MutPred		0.83		.;Loss of sheet (P = 0.0457);
MVP		0.99
MPC		0.15
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.61
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs62642574; hg19: chr1-94490550;