rs1801466

Variant names:

• chr1-94010911-T-A
• rs1801466
• NM_000350.3:c.5603A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP4_Strong BA1

The NM_000350.3(ABCA4):​c.5603A>T​(p.Asn1868Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0558 in 1,613,960 control chromosomes in the GnomAD database, including 2,989 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.040 (167 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2822 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:7 B:9 O:2
• Conservation: PhyloP100: 3.42
• Publications: 140 publications found

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 Gene-Disease associations (from GenCC):

• ABCA4-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa 19

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Stargardt disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000350.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 578 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: -0.65813 (below the threshold of 3.09). Trascript score misZ: 1.3628 (below the threshold of 3.09). GenCC associations: The gene is linked to cone-rod dystrophy 3, retinitis pigmentosa 19, ABCA4-related retinopathy, severe early-childhood-onset retinal dystrophy, cone-rod dystrophy, Stargardt disease, retinitis pigmentosa.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0069182813).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.5603A>T	p.Asn1868Ile	missense_variant	Exon 40 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.5381A>T	p.Asn1794Ile	missense_variant	Exon 39 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.5603A>T	p.Asn1868Ile	missense_variant	Exon 40 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000465352.1	n.19A>T		non_coding_transcript_exon_variant	Exon 1 of 6	5

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6143 AN: 151992 Hom.: 167 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0350

GnomAD2 exomes AF: 0.0426 AC: 10696 AN: 251362 AF XY: 0.0430

Gnomad AFR exome AF: 0.00990

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0357

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0394

Gnomad NFE exome AF: 0.0674

Gnomad OTH exome AF: 0.0527

GnomAD4 exome AF: 0.0574 AC: 83918 AN: 1461850 Hom.: 2822 Cov.: 36 AF XY: 0.0565 AC XY: 41063 AN XY: 727226

African (AFR) AF: 0.00860 AC: 288 AN: 33474

American (AMR) AF: 0.0224 AC: 1001 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 835 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0190 AC: 1641 AN: 86258

European-Finnish (FIN) AF: 0.0402 AC: 2147 AN: 53418

Middle Eastern (MID) AF: 0.0447 AC: 258 AN: 5766

European-Non Finnish (NFE) AF: 0.0674 AC: 74936 AN: 1111994

Other (OTH) AF: 0.0465 AC: 2810 AN: 60382

GnomAD4 genome AF: 0.0404 AC: 6141 AN: 152110 Hom.: 167 Cov.: 32 AF XY: 0.0380 AC XY: 2823 AN XY: 74364

African (AFR) AF: 0.0112 AC: 466 AN: 41504

American (AMR) AF: 0.0261 AC: 399 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4812

European-Finnish (FIN) AF: 0.0406 AC: 430 AN: 10588

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0663 AC: 4509 AN: 67980

Other (OTH) AF: 0.0347 AC: 73 AN: 2106

Alfa AF: 0.0579 Hom.: 219

Bravo AF: 0.0380

TwinsUK AF: 0.0631 AC: 234

ALSPAC AF: 0.0633 AC: 244

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.0665 AC: 572

ExAC AF: 0.0445 AC: 5408

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.0647

EpiControl AF: 0.0663

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:7 Benign:9 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Benign:2 Other:1

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant in the ABCA4 gene that is indicated below was identified in this patient and is not currently known to cause an ABCA4-related disorder. The variant is observed in 8,580/129,074 (6.65%) alleles from individuals of non-Finnish European background and in 11,928/282,712 (4.22%) global alleles, including 364 homozygous individuals, in large population cohorts (Lek et al., 2016). However, some publications theorize N1868I may cause hypomorphic retinal dystrophy only when in trans with a pathogenic ABCA4 variant (Zernant et al., 2017; Runhart et al., 2018). Individuals who had the N1868I variant in trans with another ABCA4 pathogenic variant were reported to have late-onset Stargardt disease (Zernant et al., 2017; Runhart et al,. 2018).; This variant is associated with the following publications: (PMID: 26780318, 21330655, 32845050, 28118664, 11328725, 28446513, 27775217, 24265693, 11017087, 29555955, 29971439, 23443024, 30204727, 30480703, 30480704, 29925512, 30670881, 30643219, 31618761, 31456290, 32467599, 32037395) -

Dec 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe early-childhood-onset retinal dystrophy Pathogenic:2 Uncertain:1 Other:1

Jun 23, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Established risk allele

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous with NM_000350.3:c.67-2A>G -

Sep 10, 2018

Molecular Vision Laboratory

Significance: other

Review Status: no assertion criteria provided

Collection Method: clinical testing

Asn1868Ile has been found to be associated with autosomal recessive Stargardt disease (STGD1). Its presence explained >40% of monoallelic ABCA4 carriers in two separate STGD1 cohorts. Penetrance was estimated to be less than 5% based on expected incidence of Asn1868Ile combinations with severe ABCA4 mutations and estimated prevalence of cases due to these combinations in a STGD1 cohort. hypomorphic allele

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt disease Pathogenic:1 Uncertain:1

Oct 01, 2024

Lab De Baere, Eye and Developmental Genetics Lab, Ghent University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

ACMG/AMP guidelines: PP4_PP, BS4, PM3_PS -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

ABCA4-related disorder Pathogenic:1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Mar 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Established risk allele

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is reported with a global allele frequency of 4.2% in gnomAD, with the highest population frequency being 6.6% in individuals of European (Non-Finnish) descent, including hundreds of homozygous individuals. Allele frequencies this high are most often associated with variants that are considered benign for Mendelian disease. However, statistical analyses have shown that this variant is significantly enriched in Stargardt patient populations compared to controls (Webster et al. 2001. PubMed ID: 11328725; Aguirre-Lamban et al. 2011. PubMed ID: 21330655). Large cohort studies of individuals with only one known pathogenic variant in ABCA4 found that this c.5603A>T (p.Asn1868Ile) variant could explain ~50% of those missing heritability cases (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Despite the enrichment in the patient population, the very high allele frequency has been used to estimate that the penetrance of this variant is less than 5% (Runhart et al. 2018. PubMed ID: 29971439). Additionally, it has been demonstrated that patients who harbor this variant have a more mild phenotype and an average age of onset in the 4th decade compared to the typical juvenile-onset associated with ABCA4 disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Functional studies have shown that this variant causes a small but significant decrease in the ATPase activity (Sun et al. 2000. PubMed ID: 11017087) and a decrease in substrate binding ability (Garces et al. 2021. PubMed ID: 33375396). This variant has often been found in cis with other ABCA4 variants such as c.2588G>C, c.5461-10T>C, and many others; forming a complex allele which can modify the penetrance and severity of disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Given all the evidence, we interpret c.5603A>T (p.Asn1868Ile) as a risk variant for mild and late-onset disease when in trans with a severe variant. -

not specified Benign:2

Nov 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCA4 c.5603A>T (p.Asn1868Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.043 in 251362 control chromosomes in the gnomAD database, including 328 homozygotes. The observed variant frequency is approximately 30.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA4 causing Stargardt Disease phenotype (0.0014). c.5603A>T has been reported in the literature in individuals affected with Stargardt Disease and related disorders (e.g. Webster_2001, Zernant_2017). These reports do not provide unequivocal conclusions about association of the variant with Stargardt Disease. Co-occurrences with multiple other pathogenic variants have been reported in cis, providing supporting evidence for a benign role. Publications report experimental evidence evaluating an impact on protein function (e.g. Sun_2000, Garces_2020). These results showed little or no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 11328725, 33375396, 11017087, 28446513). ClinVar contains an entry for this variant (Variation ID: 99390). Based on the evidence outlined above, the variant was classified as likely benign. -

May 20, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:1

Apr 01, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Asn1868Ile 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: PS3, PM3, PM3, BP2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Age related macular degeneration 2 Uncertain:1

Jun 27, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP2,PP3,BS1. -

ABCA4-related retinopathy Uncertain:1

Apr 01, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cone-rod dystrophy 3 Uncertain:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous. -

Retinal dystrophy Uncertain:1

Jan 01, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis Pigmentosa, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-Rod Dystrophy, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt Disease, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macular degeneration Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Uncertain	0.67	D;D
Eigen	Benign	0.026
Eigen_PC	Benign	-0.031
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0069	T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.4	.;M
PhyloP100		3.4
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.9	.;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.46	.;P
Vest4		0.21
MPC		0.41
ClinPred		0.050	T
GERP RS		4.8
Varity_R		0.75
gMVP		0.80
Mutation Taster		=42/58	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801466; hg19: chr1-94476467; COSMIC: COSV107460998; COSMIC: COSV107460998;