1-94011395-A-G

Variant names:

• chr1-94011395-A-G
• rs1800728
• NM_000350.3:c.5461-10T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_000350.3(ABCA4):​c.5461-10T>C variant causes a intron change. The variant allele was found at a frequency of 0.000535 in 1,613,338 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Scores: Splicing: ADA: 0.007673
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:38 O:2
• Conservation: PhyloP100: 7.03

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 Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 1-94011395-A-G is Pathogenic according to our data. Variant chr1-94011395-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94011395-A-G is described in Lovd as [Likely_pathogenic]. Variant chr1-94011395-A-G is described in Lovd as [Pathogenic]. Variant chr1-94011395-A-G is described in Lovd as [Likely_benign]. Variant chr1-94011395-A-G is described in Lovd as [Pathogenic]. Variant chr1-94011395-A-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.5461-10T>C		intron_variant	Intron 38 of 49	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.5239-10T>C		intron_variant	Intron 37 of 48		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.5461-10T>C		intron_variant	Intron 38 of 49	1	NM_000350.3	ENSP00000359245.3

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 151738 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000227 AC: 57 AN: 250882 Hom.: 0 AF XY: 0.000310 AC XY: 42 AN XY: 135630

Gnomad AFR exome AF: 0.000123

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: 0.000486

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000561 AC: 820 AN: 1461600 Hom.: 1 Cov.: 32 AF XY: 0.000535 AC XY: 389 AN XY: 727096

Gnomad4 AFR exome AF: 0.0000597

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: 0.000720

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000283 AC: 43 AN: 151738 Hom.: 0 Cov.: 32 AF XY: 0.000257 AC XY: 19 AN XY: 74068

Gnomad4 AFR AF: 0.000170

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000428 Hom.: 0

Bravo AF: 0.000249

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:38 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9 Other:2

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Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A study examining the RNA from fibroblast cells from individuals harboring the c.5461-10 T>C variant identified a reduction in full-length mRNA and the presence of alternatively spliced mRNAs where exons 39-40 were skipped (Aukrust et al., 2017); A minigene splice assay in HEK293T cells showed the c.5461-10 T>C variant construct had 100% exon 39 skipping, which was confirmed by cDNA sequencing (Sangermano et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 28044389, 15494742, 18024811, 27775217, 15614537, 26976702, 10090887, 11328725, 20696155, 26261413, 25082885, 10958763, 29162642, 29461686, 29925512, 22328824, 11527935, 22264887, 19074458, 23695285, 24713488, 26393467, 15161829, 26568636, 23918662, 26872967, 26527198, 26311262, 27583828, 25097241, 23591405, 25363634, 28130426, 29126757, 28446513, 32467599, 32141364, 28947085, 29310964, 28341476, 30093795, 30634128, 30643219, 31618761, 30204727, 30576320, 31980526, 30718709, 31589614, 32619608, 34570182, 32783370, 33851411, 34198153) -

Apr 13, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 38 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs1800728, gnomAD 0.05%). This variant has been observed in individuals with Stargardt disease (PMID: 10958763, 22328824, 23443024, 23695285, 29310964). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS38-10T>C. ClinVar contains an entry for this variant (Variation ID: 92870). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26976702, 27775217, 29461686). For these reasons, this variant has been classified as Pathogenic. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA4: PM3:Very Strong, PM2, PS3:Supporting -

-

Human Development and Health, University of Southampton

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 24, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe early-childhood-onset retinal dystrophy Pathogenic:7

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200) and other eye conditions (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. (PMID: 31522899). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Patient derived fibroblasts demonstrated two possible splicing outcomes, skipping of exon 39 or skipping of both exons 39 and 40 (PMID: 27775217, 36209838). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (62 heterozygotes, 0 homozygotes). (SP) 0704 - Another splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. c.5461-10T>G has been reported once in ClinVar as pathogenic. This variant was identified in an individual affected with cone rod dystrophy. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic many times (ClinVar) and is seen in the literature in compound heterozygous individuals, most commonly presenting with autosomal recessive Stargardt disease 1 (MIM#248200) (PMID: 31766579). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The ABCA4 c.5461-10T>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PS3, PM3-S. Based on this evidence we have classified this variant as Pathogenic. -

Jan 17, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous with NM_000350.3:c.67-2A>G._x000D_ Criteria applied: PS3, PS4, PM3_STR, PM2_SUP, PP1 -

Jan 01, 2016

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous c.5461-10T>C variant in ABCA4 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with Stargardt disease. This variant has been identified in 0.02278% (63/276528) of chromosomes and by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1800728). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The allele frequency of this variant in a cohort of 139 individuals diagnosed with Stargardt disease and multiple missense variants in the ABCA4 gene was approximately 5% (PMID: 29925512). The presence of this variant in combination with a likely pathogenic variant increases the likelihood that the c.5461-10T>C variant is pathogenic. In vitro functional studies provide some evidence that the c.5461-10T>C variant may impact protein function by causing abnormal splicing of Exon 39 and 40 in many cell types, leading to a frameshift and early termination of the protein (PMID: 29461686). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3, PM3_Supporting (Richards 2015). -

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Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Retinal dystrophy Pathogenic:5

Jan 21, 2015

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 16, 2019

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

- -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3,PS1,PM3(strong), PM2, PP1 -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Age related macular degeneration 2 Pathogenic:3

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: PS3,PS4,PM3_STR,PM2_SUP,PP1 -

Sep 01, 2016

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 23, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM3,PP4. -

Cone-rod dystrophy 3 Pathogenic:3

Jul 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 23, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 03, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous with NM_000350.3:c.1822T>A. -

Macular dystrophy Pathogenic:2

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Stargardt disease Pathogenic:2

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 24, 2023

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Clinical significance based on ACMG v2.0 -

Inborn genetic diseases Pathogenic:1

Nov 01, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5461-10T>C intronic alteration results from a T to C substitution 10 nucleotides before coding exon 39 of the ABCA4 gene. Based on data from gnomAD, the C allele has an overall frequency of 0.022% (62/282194) total alleles studied. The highest observed frequency was 0.045% (58/128638) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other ABCA4 variants in individuals with Stargardt disease and/or clinical features consistent with ABCA4-related retinal dystrophy (Jonsson, 2013; Heathfield, 2013; Sangermano, 2016; Stone, 2017; Khan, 2018; Fujinami, 2019; Pfau, 2022). This nucleotide position is highly conserved in available vertebrate species. A functional study demonstrates this variant results in exon skipping (Sangermano, 2016). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, this alteration is classified as pathogenic. -

Retinitis pigmentosa 19 Pathogenic:1

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Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign concentric annular macular dystrophy Pathogenic:1

Jan 19, 2015

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Pathogenic:1

Sep 23, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCA4-related disorder Pathogenic:1

Jun 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCA4 c.5461-10T>C variant is predicted to interfere with splicing. This intronic variant is also known as IVS38-10T>C and has been frequently reported in both the homozygous and compound heterozygous states in patients with Stargardt disease (see for examples Rivera et al. 2000. PubMed ID: 10958763; Roberts et al. 2012. PubMed ID: 22328824; Heathfield et al. 2013. PubMed ID: 23695285). A functional study using a mini-gene assay revealed that this variant causes exon skipping and results in truncated ABCA4 protein (Sangermano et al. 2016. PubMed ID: 26976702, Figure 4). This variant has been interpreted as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/92870). This variant is reported in 0.045% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given all the evidence, we interpret c.5461-10T>C 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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	16
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0077
dbscSNV1_RF	Benign	0.096
SpliceAI score (max)		0.020		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: rs1800728; hg19: chr1-94476951;