rs61750146

Positions:

chr1-94029522-A-G

Variant summary

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

The NM_000350.3(ABCA4):c.4462T>C(p.Cys1488Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,609,386 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. C1488F) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000096 ( 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: 9.16

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 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94029521-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 1-94029522-A-G is Pathogenic according to our data. Variant chr1-94029522-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94029522-A-G is described in Lovd as [Likely_pathogenic]. Variant chr1-94029522-A-G is described in Lovd as [Pathogenic]. Variant chr1-94029522-A-G is described in Lovd as [Pathogenic]. Variant chr1-94029522-A-G 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.4462T>C	p.Cys1488Arg	missense_variant	30/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.4240T>C	p.Cys1414Arg	missense_variant	29/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.4462T>C	p.Cys1488Arg	missense_variant	30/50	1	NM_000350.3	ENSP00000359245.3		P78363

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152248

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:

0.00000820

AC:

AN:

243976

Hom.:

AF XY:

0.00000760

AC XY:

AN XY:

131518

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000961

AC:

AN:

1457138

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

724272

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:

0.0000588

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000811

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

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:

0.0000363

Hom.:

ExAC

AF:

0.0000165

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:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1488 of the ABCA4 protein (p.Cys1488Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with ABCA4-related conditions (PMID: 22449572, 28559085, 29555955, 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: 99284). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ABCA4: PM3:Very Strong, PM1, PM2, PM5, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2016	The C1488R pathogenic variant in the ABCA4 gene has been published previously in association with Stargardt disease (Lewis et al., 1999; Briggs et al., 2001; Webster et al., 2001). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. C1488R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies have shown that C1488R results in lowered ATPase activity compared to wild type (Sun et al., 2000). Missense variants in the same codon (C1488Y/F) and in nearby residues (P1486L, C1490Y) have been reported in the Human Gene Mutation Database in association with Stargardt disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -

Retinal dystrophy

Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -

Severe early-childhood-onset retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 15, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -

ABCA4-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2024

The ABCA4 c.4462T>C variant is predicted to result in the amino acid substitution p.Cys1488Arg. This variant has been reported in multiple individuals with ABCA4-related retinal disease or Stargardts disease (for examples, see Lewis et al. 1999. PubMed ID: 9973280; Bertelsen et al 2014. PubMed ID: 24713488; Supplementary Table 1, Birtel et al 2018. PubMed ID: 29555955). Variants impacting the same amino acid have also been classified as pathogenic or likely pathogenic for ABCA4-related retinal disease (c.4463G>T, p.Cys1488Phe; ClinVar ID: 99286 and c.4463G>A, p.Cys1488Tyr; ClinVar ID: 99285). This variant is reported in 0.0024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Retinitis pigmentosa 19

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099284, PMID:9973280, PS1_S). Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099285,VCV000099286, PMID:10958763,11328725, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93, 3CNET: 0.99, PP3_P). A missense variant is a common mechanism associated with Retinitis pigmentosa 19 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000011, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.55

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

.;M

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-11

.;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.87

.;P

Vest4

0.94

MVP

0.98

MPC

0.62

ClinPred

1.0

GERP RS

5.2

Varity_R

0.94

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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