rs61749409

chr1-94062710-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000350.3(ABCA4):c.1804C>T(p.Arg602Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,613,984 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. R602Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 3.97

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 16 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 chr1-94062709-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 1-94062710-G-A is Pathogenic according to our data. 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. Variant chr1-94062710-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94062710-G-A is described in Lovd as [Pathogenic]. Variant chr1-94062710-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94062710-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.1804C>T	p.Arg602Trp	missense_variant	13/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.1804C>T	p.Arg602Trp	missense_variant	13/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.1804C>T	p.Arg602Trp	missense_variant	13/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.1804C>T	p.Arg602Trp	missense_variant	13/19

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 250870 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461842 Hom.: 0 Cov.: 37 AF XY: 0.0000234 AC XY: 17 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74306

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000288 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 602 of the ABCA4 protein (p.Arg602Trp). This variant is present in population databases (rs61749409, gnomAD 0.03%). This missense change has been observed in individuals with Stargardt disease and autosomal recessive retinitis pigmentosa (PMID: 16103129, 23755871). ClinVar contains an entry for this variant (Variation ID: 99084). 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). 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: 20696155, 22449572, 23982839, 25472526, 25910913). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2023	Published functional studies demonstrate a damaging effect suggestive of protein misfolding (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: 24444108, 31429209, 33706644, 28118664, 28041643, 28181551, 28947085, 28446513, 29186038, 23755871, 29641573, 29114839, 30093795, 28559085, 28838317, 32036094, 32581362, 32845050, 31216405, 34327195, 33781268, 31589614, 32619608, 33090715, 33301772, 33261146, 35657619, 35119454, 20696155, 25472526, 36338671, 22449572, 23982839, 34906470, 25910913, 9973280, 16103129, 23695285) -
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	Revvity Omics, Revvity	Oct 15, 2019	- -
not provided, no classification provided	literature only	Retina International	-	- -

Severe early-childhood-onset retinal dystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace arginine with tryptophan at codon 602 of the ABCA4 protein, p.(Arg602Trp). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is present in the extracellular domain. There is a moderate physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort 0.004%, which is consistent with recessive disease (rs61749409, 11/250,870 alleles, 0 homozygotes in gnomAD v2.1). It has been reported compound heterozygous with another pathogenic allele and homozygous most commonly in Stargardt disease cases, and also cases of cone-rod dystrophy and retinitis pigmentosa co-segregating with disease (PMID: 9973280, 16103129, 23695285). In vitro functional assays demonstrate that the missense substitution prevents correct localisation of the protein in to the rod outer segment, and perturbs ATPase activity (PMID: 16103129). Additionally, multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PS3_Supporting, PP1, PP3. -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The ABCA4 c.1804C>T 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: PM1, PM2, PS3, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2016	- -

Retinitis pigmentosa 19 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Pangenia Genomics, Pangenia Inc.	Nov 18, 2021	The ABCA4, c.1804C>T (p.Arg602Trp) variant is at extremely low frequency in population database. In vitro functional studies demonstrated that this variant results in protein mis-folding and mis-localization [PMID: 16103129]. This variant has been observed in many individuals with autosomal recessive retinopathy, in homozygosity, or with another variant in ABCA4 gene, including null variants and missense variants [PMID: 16103129, 30093795, 9973280, 23755871, 32619608, 29186038]. This variant has been found to co-segregate with retinitis pigmentosa, Stargardt disease 1 or Cone-rod dystrophy in multiple families (PMID: 16103129, 23755871, 32619608, 29114839). Multiple lines of computational evidence support a deleterious effect on the gene/gene product (REVEL = 0.934). This variant has multiple submissions in ClinVar (Variation ID: 99084). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099084). The variant has been reported to be in trans with other pathogenic variant(s) as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 16103129). A different missense change at the same codon (p.Arg602Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099085). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Retinal dystrophy Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 16, 2019	- -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2018

- -

ABCA4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 05, 2022

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 16103129) - PS3.The c.1804C>T;p.(Arg602Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 99084; PMID: 28181551; 28118664; 28041643; 24444108; 23982839; 23755871; 9973280) - PS4. The variant is present at low allele frequencies population databases (rs61749409 – gnomAD 0.0004385%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg602Trp) was detected in trans with a pathogenic variant (PMID: 28181551; PMID: 16103129; PMID: 24444108; PMID: 23982839; PMID: 23755871) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 16103129) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Cone-rod dystrophy 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Molecular Genetics, University of Zurich

Jan 30, 2021

- -

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

Mar 22, 2022

- -

Stargardt disease Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Jul 24, 2023

Clinical significance based on ACMG v2.0 -

Retinitis pigmentosa Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Apr 01, 2021

The p.Arg602Trp variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM1, PM2, PS3, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0030	D;.
Polyphen		0.64	P;.
Vest4		0.84
MutPred		0.87		Loss of disorder (P = 0.0812);Loss of disorder (P = 0.0812);
MVP		0.99
MPC		0.47
ClinPred		0.79	D
GERP RS		5.0
Varity_R		0.65
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61749409; hg19: chr1-94528266; COSMIC: COSV100933342; COSMIC: COSV100933342;