rs61751404

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong

The NM_000350.3(ABCA4):c.4918C>T(p.Arg1640Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,614,098 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,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1640Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic; other criteria provided, multiple submitters, no conflicts P:18O:2

Conservation

PhyloP100: 2.58

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 Pathogenic. Variant got 14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94021339-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 1-94021340-G-A is Pathogenic according to our data. Variant chr1-94021340-G-A is described in ClinVar as [Likely_pathogenic, other]. Clinvar id is 99330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94021340-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94021340-G-A is described in Lovd as [Likely_benign]. Variant chr1-94021340-G-A is described in Lovd as [Pathogenic]. Variant chr1-94021340-G-A is described in Lovd as [Pathogenic]. Variant chr1-94021340-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.4918C>T	p.Arg1640Trp	missense_variant	35/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.4696C>T	p.Arg1566Trp	missense_variant	34/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.4918C>T	p.Arg1640Trp	missense_variant	35/50	1	NM_000350.3	ENSP00000359245.3	P78363
ABCA4	ENST00000460514.1 linkuse as main transcript	n.412C>T		non_coding_transcript_exon_variant	6/7	5
ABCA4	ENST00000470771.1 linkuse as main transcript	n.28C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251420

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000665

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000691

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic; other

Submissions summary: Pathogenic:18Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ABCA4: PM3:Very Strong, PM2, PM5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2017	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1640 of the ABCA4 protein (p.Arg1640Trp). This variant is present in population databases (rs61751404, gnomAD 0.007%). This missense change has been observed in individuals with ABCA4-related conditions (PMID: 9781034, 28041643, 28559085, 29925512). ClinVar contains an entry for this variant (Variation ID: 99330). 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: 11687513). This variant disrupts the p.Arg1640 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10711710, 11527935, 23755871, 26103963, 28118664). 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	Oct 04, 2018	The R1640W pathogenic variant in the ABCA4 gene has been reported previously in autosomal recessive Stargardt disease in affected individuals when in the homozgyous state or when in trans with another pathogenic variant (Battu et al., 2015; Fujinami et al., 2013; Rozet et al., 1998). The R1640W variant has been reported on the same allele (in cis) with the W1408R variant in families with Stargardt disease, and in a family presenting with both Stargardt disease and retinitis pigmentosa, when in trans with another pathogenic variant (Valverde et al, 2006; Shroyer et al, 2001). Shroyer et al. (2001) showed very little protein from cells transfected with the W1408R and R1640W variants in cis; however, proteins bearing only the W1408R or the R1640W variants appear to have mild or moderate defects in expression or stability. The R1640W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1640W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret R1640W as a pathogenic variant. -

Severe early-childhood-onset retinal dystrophy

Pathogenic:4

Pathogenic, no assertion criteria provided	research	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	-	- -
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 1640 of the ABCA4 protein, p.(Arg1640Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and there is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.003%, consistent with recessive disease (rs61751404, 8/251,420 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in the homozygous state and compound heterozygous with a second pathogenic allele in multiple Stargardt disease cases (PMID: 9781034, 10090887, 11687513, 21873672). The missense change causes reduced protein expression and ATPase activity in in vitro functional assays (PMID: 11687513). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). A different missense change at the same amino acid residue (p.Arg1640Gln) determined to be pathogenic has been seen before (ClinVar ID: 99331). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PM2, PM5, PS3_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The ABCA4 c.4918C>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: PM2, PP3, PS3, PM1, PM3-S. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200), cone-rod dystrophy 3 (MIM#604116), fundus flavimaculatus (MIM#248200), early-onset severe retinal dystrophy (MIM#248200) and retinitis pigmentosa 19 (MIM#601718). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (8 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (8 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC2_membrane_3 domain (Protein DataBank). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals diagnosed with Stargardt disease (ClinVar, PMIDs: 23769331, 25066811, 25922843, 29854428, 30060493, 30834176, 31766579). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Retinal dystrophy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Jan 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 16, 2019	- -

Stargardt disease

Pathogenic:3

Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
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 -

ABCA4-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2024

The ABCA4 c.4918C>T variant is predicted to result in the amino acid substitution p.Arg1640Trp. This variant has been reported many times to be causative for autosomal recessive Stargardt disease or macular and cone/cone-rod dystrophy (see for examples: Rozet et al. 1998. PubMed ID: 9781034; Alapati et al. 2014. PubMed ID: 25082885; Table S1, Birtel et al. 2018. PubMed ID: 29555955). This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Leber congenital amaurosis

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Cone-rod dystrophy 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Mar 28, 2023

Criteria applied: PM3_VSTR,PM5,PS3_SUP,PM2_SUP,PP3 -

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

Aug 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

D;D

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.2

.;M

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.0

.;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

.;D

Vest4

0.93

MutPred

0.88

.;Loss of disorder (P = 0.0118);

MVP

0.96

MPC

0.47

ClinPred

0.79

GERP RS

3.4

Varity_R

0.68

gMVP

0.91

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

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