rs1553186896

Positions:

• chr1-94005490-A-C
• chr1-94005490-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM5 PP3_Strong PP5_Moderate

The NM_000350.3(ABCA4):​c.6098T>G​(p.Leu2033Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,876 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. L2033P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.18

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 10 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94005490-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438104.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 1-94005490-A-C is Pathogenic according to our data. Variant chr1-94005490-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 438105.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-94005490-A-C is described in Lovd as [Pathogenic]. Variant chr1-94005490-A-C is described in Lovd as [Likely_pathogenic]. Variant chr1-94005490-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.6098T>G	p.Leu2033Arg	missense_variant	44/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.5876T>G	p.Leu1959Arg	missense_variant	43/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.6098T>G	p.Leu2033Arg	missense_variant	44/50	1	NM_000350.3	P1
ABCA4	ENST00000465352.1	n.514T>G		non_coding_transcript_exon_variant	5/6	5
ABCA4	ENST00000484388.1	n.212T>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461876 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2023

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 438105). This missense change has been observed in individual(s) with cone-rod dystrophy and/or Stargardt disease (PMID: 22229821, 25346251, 28041643, 30718709, 32581362). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2033 of the ABCA4 protein (p.Leu2033Arg). -

Retinal dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Stargardt disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.4	.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.84		.;Gain of methylation at L2033 (P = 0.019);
MVP		0.99
MPC		0.56
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1553186896; hg19: chr1-94471046;