rs61748558

Positions:

chr1-94063224-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1PM5PP3_StrongPP5_Very_Strong

The NM_000350.3(ABCA4):c.1648G>A(p.Gly550Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,974 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G550E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 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: 7.57

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 18 ACMG points.

PS1

Transcript NM_000350.3 (ABCA4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94063223-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2708916.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 1-94063224-C-T is Pathogenic according to our data. Variant chr1-94063224-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94063224-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94063224-C-T 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.1648G>A	p.Gly550Arg	missense_variant	12/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.1648G>A	p.Gly550Arg	missense_variant	12/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.1648G>A	p.Gly550Arg	missense_variant	12/50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000649773.1 linkuse as main transcript	c.1648G>A	p.Gly550Arg	missense_variant	12/19			ENSP00000496882.1		A0A3B3IRV8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

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:

0.00000398

AC:

AN:

251436

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135886

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

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:

0.0000232

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2021	Not observed at significant frequency in large population cohorts (gnomAD); 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: 24713488, 17982420, 22229821, 28559085, 30093795, 31589614, 33732702, 22264887, 24317291, 32619608, 31968401, 11726554, 11527935, 15192030, 33090715, 29925512) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 550 of the ABCA4 protein (p.Gly550Arg). This variant is present in population databases (rs61748558, gnomAD 0.003%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 11726554, 28559085, 29925512). 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: 99070). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

ABCA4-related disorder

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 25, 2018	The ABCA4 c.1648G>A (p.Gly550Arg) missense variant has been identified in at least seven studies in which it is found in a total of seven individuals including in three in a compound heterozygous state with a known pathogenic variant and four in a heterozygous state with an undetected second allele (Shroyer et al., 2001; Briggs et al., 2001; Stenirri et al., 2004; Thiadens et al 2012; Bertelsen et al. 2014; Fujinami et al., 2015; Salles et al. 2018). Six of these individuals exhibited Stargardt disease and the seventh exhibited generalized choriocapillaris dystrophy. The p.Gly550Arg variant was absent from 100 control chromosomes (Shroyer et al., 2001) and is reported at a frequency of 0.00006 in the South Asian population of the Exome Aggregation Consortium, but this is based on one allele, so the variant is presumed to be rare. Based on the evidence, the p.Gly550Arg variant is classified as likely pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 14, 2023	The ABCA4 c.1648G>A variant is predicted to result in the amino acid substitution p.Gly550Arg. This variant has been reported many times as causative for autosomal recessive retinal dystrophy (see for examples Shroyer et al. 2001. PubMed ID: 11726554; Bertelsen et al. 2014. PubMed ID: 24713488; Table S1 in Stone. 2017. PubMed ID: 28559085; Zhu et al. 2021. PubMed ID: 33732702). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94528780-C-T). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99070/). Given the evidence, we interpret c.1648G>A (p.Gly550Arg) as pathogenic. -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2008	- -

Stargardt disease 3

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana

- -

Retinitis pigmentosa 19

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Aug 21, 2017

- -

Cone-rod dystrophy 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

The Cell Therapy Center, The University of Jordan

Mar 15, 2019

This variant was classified as pathogenic based on its segregation with the disease, allele frequency, and in-silico tools. One patient with this variant was found to have sectoral RP features. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.53

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;.

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.0

D;.

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.025

D;.

Polyphen

0.88

P;.

Vest4

0.96

MutPred

0.91

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.94

MPC

0.50

ClinPred

1.0

GERP RS

5.0

Varity_R

0.76

gMVP

0.99

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