NM_000350.3:c.1957C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000350.3(ABCA4):c.1957C>T(p.Arg653Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,612,644 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. R653H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 6.85

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94060739-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 1-94060740-G-A is Pathogenic according to our data. Variant chr1-94060740-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94060740-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94060740-G-A is described in Lovd as [Pathogenic]. Variant chr1-94060740-G-A is described in Lovd as [Likely_benign]. Variant chr1-94060740-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94060740-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.1957C>T	p.Arg653Cys	missense_variant	Exon 14 of 50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.1957C>T	p.Arg653Cys	missense_variant	Exon 14 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCA4	ENST00000370225.4 link	c.1957C>T	p.Arg653Cys	missense_variant	Exon 14 of 50	1	NM_000350.3	ENSP00000359245.3	P78363
ABCA4	ENST00000649773.1 link	c.1957C>T	p.Arg653Cys	missense_variant	Exon 14 of 19			ENSP00000496882.1	A0A3B3IRV8
ABCA4	ENST00000472033.1 link	n.77C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248260

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

134120

show subpopulations

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:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1460484

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726388

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000375

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Other:1

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 37498587, 35120629, 35260635, 31964843, 36460718, 32307445, 29701254, 37734845, 32531858, 26992781, 11702214, 23776498, 23499370, 27939946, 28355279, 10958763, 15192030, 19265867, 23953153, 25097154, 25444351, 18652558, 23982839, 28559085, 30204727, 32619608, 29925512, 33301772, 33375396, 35119454, 26957898) -

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 653 of the ABCA4 protein (p.Arg653Cys). This variant is present in population databases (rs61749420, gnomAD 0.003%). This missense change has been observed in individual(s) with cone rod dystrophy and Stargardt disease (PMID: 23776498, 28559085). 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: 99108). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg653 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9466990, 10413692, 19074458). 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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA4: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Severe early-childhood-onset retinal dystrophy

Pathogenic:2

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.72). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099108 /PMID: 10958763). Different missense changes at the same codon (p.Arg653His, p.Arg653Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000417982, VCV000635441 /PMID: 25346251 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Retinal dystrophy

Pathogenic:2

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCA4-related disorder

Pathogenic:1

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCA4 c.1957C>T variant is predicted to result in the amino acid substitution p.Arg653Cys. This variant has been reported in multiple individuals with Stargardt disease or ABCA4-related retinal disease (for examples, see: Huang et al. 2013. PubMed ID: 23776498; Supplementary table 2, Fujinami K et al. 2018. PubMed ID: 29925512). Functional studies demonstrate that this variant impairs N-Ret-PE binding and stimulation of ATPase activity of the protein (Garces et al. 2020. PuMed ID 33375396). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

3.2

M;.

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.0

D;.

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.84

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.93

MPC

0.53

ClinPred

0.97

GERP RS

5.9

Varity_R

0.81

gMVP

0.90

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