rs61750130

chr1-94031110-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PP3_Moderate PP5_Very_Strong

The NM_000350.3(ABCA4):c.4139C>T(p.Pro1380Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,613,962 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P1380P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:2
• Conservation: PhyloP100: 9.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000350.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 1-94031110-G-A is Pathogenic according to our data. Variant chr1-94031110-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94031110-G-A is described in Lovd as [Pathogenic]. Variant chr1-94031110-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94031110-G-A is described in Lovd as [Likely_benign]. Variant chr1-94031110-G-A is described in Lovd as [Pathogenic]. Variant chr1-94031110-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.4139C>T	p.Pro1380Leu	missense_variant	28/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.3917C>T	p.Pro1306Leu	missense_variant	27/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.4139C>T	p.Pro1380Leu	missense_variant	28/50	1	NM_000350.3	P1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 251084 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135732

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000293 AC: 429 AN: 1461766 Hom.: 0 Cov.: 32 AF XY: 0.000285 AC XY: 207 AN XY: 727156

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000299

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74358

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000314 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2023	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: 26766544, 28559085, 29925512, 31429209, 32531858, 33706644, 34315337, 35456422, 33369172, 32037395, 25283059, 15579991, 9973280, 25087612, 11527935, 28341476, 28041643, 19074458, 10396622, 16682602, 30634128, 30204727, 30718709, 11017087, 32467599, 31456290, 32581362, 33375396, 34426522, 31573552, 31589614, 32619608, 27030965, 28947085, 35119454) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1380 of the ABCA4 protein (p.Pro1380Leu). This variant is present in population databases (rs61750130, gnomAD 0.2%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 9973280, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7904). 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. -

Severe early-childhood-onset retinal dystrophy Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2006	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -

Stargardt disease Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Pathogenic, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	Jul 24, 2023	Clinical significance based on ACMG v2.0 -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

ABCA4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 21, 2018

The ABCA4 c.4139C>T (p.Pro1380Leu) missense variant has been reported in at least ten studies in which it is found in at least 38 individuals with either Stargardt disease (STGD), cone-rod dystrophy or age related macular degeneration including in five individuals in a homozygous state, at least 29 in a compound heterozygous state, and four individuals in a heterozygou state (Shroyer et al. 1999; Lewis et al. 1999; Shroyer et al. 2001; Briggs et al. 2001; Oh et al. 2004; Fingert et al. 2006; Hwang et al. 2009; Cideciyan et al. 2009; Chacón-Camacho et al. 2013; Duncker et al. 2015). The p.Pro1380Leu variant has been shown to segregate with STGD disease in at least three families (Lewis et al. 1999; Shroyer et al. 2001; Cideciyan et al. 2009). The variant has not been reported in association with retinitis pigmentosa. The p.Pro1380Leu variant was absent from at least 895 controls and is reported at a frequency of 0.001973 in the Ashkenazi Jewish population of the Genome Aggregation Database. In vitro analysis in HEK-293 cells demonstrated that the p.Pro1380Leu variant resulted in reduced expression of the protein and defective ATP binding (Sun et al. 2000). Based on the collective evidence, the p.Pro1380Leu variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mandibulofacial dysostosis with mental deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Jul 24, 2015

This variant has been observed, either as homozygous (Hwang JC et al., 2009) or compound heterozygous (Lewis RA et al., 1999) in individuals who have been diagnosed with Stargardt disease. It co-segregates with disease and was found in trans with the known pathogenic variant, G1961E (Duncker T et al., 2015). In the protein, it is present in the helical transmembrane domain 7 and is close to the nucleotide binding domain-1. Studies in HEK 293 cells showed that, compared with wild-type, the protein yield and ATP-binding capacity of this variant was reduced (Sun H et al., 2000). Finally, multiple computational algorithms predict this variant to be deleterious and its frequency in the population databases (1000 Genomes, Exome Sequencing Project [ESP] and ExAC) is either absent or very low. Therefore, this variant meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 14, 2019

- -

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

Oct 08, 2021

- -

MACULAR DEGENERATION, AGE-RELATED, 2, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.74	T
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.99	.;D
Vest4		0.97
MVP		0.99
MPC		0.33
ClinPred		0.82	D
GERP RS		5.0
Varity_R		0.35
gMVP		0.90

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

Other links and lift over

dbSNP: rs61750130; hg19: chr1-94496666;