rs760549861

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong

The NM_000350.3(ABCA4):c.5318C>T(p.Ala1773Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,990 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. A1773?) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 10.0

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 13 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity ABCA4_HUMAN there are 32 pathogenic changes around while only 0 benign (100%) in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94014684-CGC-CT is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

PP5

Variant 1-94014685-G-A is Pathogenic according to our data. Variant chr1-94014685-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94014685-G-A is described in Lovd as [Pathogenic]. Variant chr1-94014685-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94014685-G-A is described in Lovd as [Pathogenic]. Variant chr1-94014685-G-A 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.5318C>T	p.Ala1773Val	missense_variant	38/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1 linkuse as main transcript	c.5096C>T	p.Ala1699Val	missense_variant	37/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.5318C>T	p.Ala1773Val	missense_variant	38/50	1	NM_000350.3	ENSP00000359245	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251426

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000961

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1773 of the ABCA4 protein (p.Ala1773Val). This variant is present in population databases (rs760549861, gnomAD 0.05%). This missense change has been observed in individuals with ABCA4-related retinal disease (PMID: 18652558, 23419329, 28130426, 29422768). It is commonly reported in individuals of Mexican ancestry (PMID: 18652558, 23419329, 28130426, 29422768). ClinVar contains an entry for this variant (Variation ID: 236129). 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	GeneDx	Jun 05, 2024	Reported in multiple individuals with Stargardt disease from Mexico, suggesting a founder mutation effect (PMID: 23419329, 29422768); Published functional studies demonstrate a damaging effect with significant reduction of protein function (PMID: 33375396); This variant is associated with the following publications: (PMID: 26161775, 23591405, 25082829, 25301883, 23419329, 35120629, 35260635, 31964843, 36460718, 32307445, 36729443, 36087940, 36284460, 29641573, 28118664, 28130426, 24763286, 32531858, 34315337, 25283059, 26780318, 28512305, 18652558, 28327576, 29288030, 29422768, 29925512, 31736247, 31456290, 32090030, 32845068, 31589614, 32619608, 33090715, 33301772, 33732702, 35657619, 35119454, 33375396) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -

Stargardt disease

Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 08, 2020	Variant summary: ABCA4 c.5318C>T (p.Ala1773Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251426 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ABCA4 causing Stargardt disease (7.6e-05 vs 0.0014), allowing no conclusion about variant significance. c.5318C>T has been reported in the literature in numerous individuals affected with Stargardt disease (homozygotes and heterozygotes) and may be a Mexican founder mutation (Chacon-Camacho_2013, Fujinami_2019, Lopez-Rubio_2018, Stenirri_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 01, 2023	The p.Ala1773Val variant in ABCA4 has been reported in >10 individuals with Stargardt disease and/or retinal degeneration, including at least 3 compound heterozygotes and 6 homozygotes, and segregated in 4 affected relatives (Stenirri 2008, Chacón-Camacho 2013, Duncker 2015, Biswas 2017, López-Rubio 2018). This variant has been reported in ClinVar (Variation ID: 236129) and has been identified in 0.05% (16/33582) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs760549861). Although this variant is seen in the general population, its frequency is consistent with a recessive carrier frequency. Additionally, another allele the same position (p.Ala1773Glu) has been reported with a similar phenotype (Downes 2012), suggesting that changes at this position may not be tolerated. In summary, this variant is pathogenic for Stargardt disease in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong; PP1_Moderate; PP3. -

Severe early-childhood-onset retinal dystrophy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 21, 2020	- -
Pathogenic, no assertion criteria provided	research	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	-	- -

ABCA4-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2024

The ABCA4 c.5318C>T variant is predicted to result in the amino acid substitution p.Ala1773Val. This variant has been reported many times along with a second ABCA4 variant in individuals with retinal disease (see for examples: Chacón-Camacho et al. 2013. PubMed ID: 23419329; Duncker et al. 2015. PubMed ID: 25283059; Table S1, Karali et al. 2022. PubMed ID: 36460718; Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 23, 2021

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.8

.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.0

.;D

REVEL

Pathogenic

0.79

Sift

Benign

0.044

.;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

.;D

Vest4

0.92

MVP

0.93

MPC

0.41

ClinPred

0.90

GERP RS

4.7

Varity_R

0.54

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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