chr1-94005509-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong

The NM_000350.3(ABCA4):c.6079C>T(p.Leu2027Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000469 in 1,614,112 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 (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19O:1

Conservation

PhyloP100: 6.60

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 11 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000350.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

PP5

Variant 1-94005509-G-A is Pathogenic according to our data. Variant chr1-94005509-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94005509-G-A is described in Lovd as [Likely_benign]. Variant chr1-94005509-G-A is described in Lovd as [Pathogenic]. Variant chr1-94005509-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94005509-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94005509-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.6079C>T	p.Leu2027Phe	missense_variant	Exon 44 of 50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.5857C>T	p.Leu1953Phe	missense_variant	Exon 43 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCA4	ENST00000370225.4 link	c.6079C>T	p.Leu2027Phe	missense_variant	Exon 44 of 50	1	NM_000350.3	ENSP00000359245.3	P78363
ABCA4	ENST00000465352.1 link	n.495C>T		non_coding_transcript_exon_variant	Exon 5 of 6	5
ABCA4	ENST00000484388.1 link	n.193C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251402

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

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:

0.000387

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000499

AC:

730

AN:

1461828

Hom.:

Cov.:

AF XY:

0.000491

AC XY:

357

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

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:

0.000634

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000177

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000241

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:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Other:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2027 of the ABCA4 protein (p.Leu2027Phe). This variant is present in population databases (rs61751408, gnomAD 0.03%). This missense change has been observed in individuals with Stargardt disease (PMID: 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7882). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 29847635). For these reasons, this variant has been classified as Pathogenic. -

May 11, 2018

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with decreased ATPase function of the protein, reduced expression compared to wild-type, and abnormal localization to the endoplasmic reticulum (Biswas et al., 2000; Garces et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9666097, 11527935, 11702214, 29884405, 29701254, 29310964, 31429209, 32531858, 33706644, 34795310, 34946930, 35456422, 23695285, 19074458, 24713488, 14517951, 9973280, 11328725, 11726554, 10396622, 10090887, 15161829, 29555955, 29847635, 30609409, 30093795, 30060493, 29126757, 30563929, 27820952, 28559085, 32845050, 9054934, 31589614, 32810830, 33546218, 11123914, 29925512) -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCA4 p.Leu2027Phe variant was identified in 44 of 428 proband chromosomes (frequency: 0.103) from individuals or families with Stargardt Disease, Cone-Rod dystrophy or ABCA4-Associated Retinopathies (Maugeri_1999_PMID:10090887; Bertelsen_2014_PMID:24713488; Heathfield_2013_PMID:23695285, Fishman_2003_PMID:12796258). The variant was identified in dbSNP (ID: rs61751408) and in ClinVar (classified as pathogenic by EGL Genetic Diagnostics, Fulgent Genetics, GeneDx and Institute of Human Genetics, Univ. Regensburg). The variant was also identified in control databases in 56 of 282804 chromosomes at a frequency of 0.000198 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 45 of 129122 chromosomes (freq: 0.000349), African in 8 of 24968 chromosomes (freq: 0.00032), Other in 1 of 7222 chromosomes (freq: 0.000139) and Latino in 2 of 35436 chromosomes (freq: 0.000056); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Leu2027 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. However, in vitro functional studies of the L2027F variant have demonstrated biochemical defects leading to lower protein functionality and altered ATPase function (Sun_2000_PMID: 11017087; Biswas_2000_PMID: 11123914). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Severe early-childhood-onset retinal dystrophy

Pathogenic:6

Jun 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace leucine with phenylalanine at codon 2027 of the ABCA4 protein (p.Leu2027Phe). The leucine residue is highly conserved (100 vertebrates, UCSC), and located in the cytoplasmic ATP-binding cassette (ABC) transporter 2 domain. There is a small physicochemical difference between leucine and phenylalanine. The variant is present in a large population cohort at a frequency of 0.02%, which is consistent with recessive carrier frequency (rs61751408, 56/282,804 alleles, 0 homozygotes in gnomAD v2.1.1 - PM2). It is a recurrent variant that has been identified as compound heterozygous or homozygous in multiple Stargardt disease patients, with homozygous cases demonstrating a milder phenotype (PMID: 9054934, 23695285, 23769331 - PM3_VeryStrong). The missense change significantly reduces the ATPase function of the ABC transporter domain in multiple in vitro functional assays (PMID: 11017087, 11123914 - PS3). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms - PP3). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PM2, PP3. -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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). (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 leucine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3) for a recessive condition (74 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ABC transporter domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with autosomal recessive Stargardt disease (ClinVar, PMID: 23695285). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PM3_STR,PP3 -

Cone-rod dystrophy 3

Pathogenic:2

Jun 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Pathogenic:2

Aug 12, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Age related macular degeneration 2

Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt disease

Pathogenic:1

Nov 10, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu2027Phe variant in ABCA4 has been reported in over 30 individuals with Stargardt disease, including 28 compound heterozygous and 3 homozygous individua ls (Allikmets 1997, Bertelsen 2014, Heathfield 2013, Fujinami 2013). Of note, t he individuals homozygous for this variant presented with a later onset and mild er phenotype (Fujinami 2013, Heathfield 2013). The variant has been identified i n 23/66736 of European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs61751408). Although this variant has been seen in the general population, its frequency is low enough to be consistent wit h a recessive carrier frequency. In vitro functional studies provide some evide nce that the p.Leu2027Phe variant may impact protein function (Biswas 2000). In summary, this variant meets criteria to be classified as pathogenic for Stargard t disease in an autosomal recessive manner based upon observation in patients wi th this disease and functional evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

D;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.2

.;L

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.7

.;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0020

.;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

.;D

Vest4

0.98

MVP

0.98

MPC

0.48

ClinPred

0.29

GERP RS

5.9

Varity_R

0.80

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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