rs61750142

chr1-94030452-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM5 PP5_Very_Strong

The NM_000350.3(ABCA4):c.4328G>A(p.Arg1443His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1443C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 3.43

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 12 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94030453-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1476832.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 1-94030452-C-T is Pathogenic according to our data. Variant chr1-94030452-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94030452-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94030452-C-T is described in Lovd as [Pathogenic]. Variant chr1-94030452-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.4328G>A	p.Arg1443His	missense_variant	29/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.4106G>A	p.Arg1369His	missense_variant	28/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.4328G>A	p.Arg1443His	missense_variant	29/50	1	NM_000350.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152200 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251460 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135912

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.0000241

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000683 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy Pathogenic:3

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 Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099278, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000021, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.805, 3CNET: 0.958, PP3_P). A missense variant is a common mechanism associated with Stargardt disease 1 (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

ABCA4-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2019	Across a selection of the literature, the ABCA4 c.4328G>A (p.Arg1443His) missense variant has been reported in a compound heterozygous state in at least five individuals, including four affected with Stargardt disease, one described as affected with ABCA4-associated disease and one with ABCA4-associated retinopathies (Rivera et al. 2000; Testa et al. 2012; Chacón-Camacho et al. 2013; Fujinami et al. 2013; Nõupuu et al. 2014; Schulz et al. 2017). In addition Roberts et al. (2011) identified the p.Arg1443His variant in one patient allele from a cohort of 181 individuals with ABCA4-associated retinopathies. The variant was absent from 220 control individuals and is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Arg1443 residue is noted to be well conserved. Biswas-Fiss et al. (2010) compared the ABCA4 wild type structure with that of three variant structures, including the p.Arg1443His variant using CD spectral analysis. The p.Arg1443His variant structure was shown to be significantly altered with loss of alpha-helical secondary structure. The same study also demonstrated decreased binding affinity to its substrate. Based on the collective evidence, the p.Arg1443His 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 22, 2023	The ABCA4 c.4328G>A variant is predicted to result in the amino acid substitution p.Arg1443His. This variant was reported in the compound heterozygous state in several individuals with autosomal recessive ABCA4-related disorders (Rivera et al 2000. PubMed ID: 10958763; Fujinami K et al 2018. PubMed ID: 29925512; Salles MV et al 2018. PubMed ID: 30093795; Fujinami K et al 2013. PubMed ID: 23982839; Testa F et al 2012. PubMed ID: 22661472; Nõupuu K et al 2014. PubMed ID: 25301883; ). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94496008-C-T). This variant is interpreted as likely pathogenic. -

Retinal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 06, 2019	- -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1443 of the ABCA4 protein (p.Arg1443His). This variant is present in population databases (rs61750142, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive Stargardt disease (PMID: 15161829, 22661472, 23419329, 23982839, 28118664, 29925512). 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: 99278). 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: 20404325). For these reasons, this variant has been classified as Pathogenic. -

Age related macular degeneration 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Pathogenic	0.89	D
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.17	T;T
Polyphen		1.0	.;D
Vest4		0.72
MVP		0.97
MPC		0.48
ClinPred		0.95	D
GERP RS		3.7
Varity_R		0.14
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs61750142; hg19: chr1-94496008; COSMIC: COSV64673800; COSMIC: COSV64673800;