NM_000350.3:c.6316C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000350.3(ABCA4):c.6316C>T(p.Arg2106Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,614,108 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. R2106H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 2.93

Publications

22 publications found

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 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

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94001071-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 377409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

PP5

Variant 1-94001072-G-A is Pathogenic according to our data. Variant chr1-94001072-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 99447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.6316C>T	p.Arg2106Cys	missense_variant	Exon 46 of 50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.6094C>T	p.Arg2032Cys	missense_variant	Exon 45 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.6316C>T	p.Arg2106Cys	missense_variant	Exon 46 of 50	1	NM_000350.3	ENSP00000359245.3		P78363

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000995

AC:

AN:

251238

AF XY:

0.0000957

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000773

AC:

113

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000638

AC:

AN:

1112004

Other (OTH)

AF:

0.0000662

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000302

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000842

AC:

AN:

41562

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000178

Hom.:

Bravo

AF:

0.000280

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Nov 19, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11379881, 9054934, 23143460, 25066811, 28044389, 28355279, 25283059, 30903310, 34426522, 31589614, 29114839, 32619608) -

Jan 23, 2025

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 2106 of the ABCA4 protein (p.Arg2106Cys). This variant is present in population databases (rs61750648, gnomAD 0.08%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 11379881, 23143460, 25283059, 28355279). 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: 99447). 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: 11017087). This variant disrupts the p.Arg2106 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 26161775, 28327576), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Oct 31, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:3

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 04, 2018

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

Oct 18, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3 -

ABCA4-related retinopathy

Pathogenic:1

Jul 05, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Severe early-childhood-onset retinal dystrophy

Pathogenic:1

Dec 20, 2021

MGZ Medical Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Stargardt disease

Pathogenic:1

Mar 09, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg2106Cys variant in ABCA4 has been reported in at least 5 individuals (compound heterozygotes) with Stargardt disease (Allikmets 1997, Zernant 2011, Downes 2012, Zernant 2014, Schulz 2017). This variant has also been identified in 0.04% (4/10392) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs61750648). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for Stargardt disease in an autosomal recessive manner based upon case studies and low frequency in controls. -

Retinitis pigmentosa

Pathogenic:1

Oct 01, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG/AMP guidelines: PM2, PP3, PM5, PP1, PM3_PS -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

.;M

PhyloP100

2.9

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.8

.;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.99

MVP

0.99

MPC

0.54

ClinPred

0.59

GERP RS

5.1

Varity_R

0.93

gMVP

0.93

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over