1-94001068-C-T

Variant names:

• chr1-94001068-C-T
• rs62642564
• NM_000350.3:c.6320G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 13P and 2B. PM1 PM5 PP3 PP5_Very_Strong BP4 BS1_Supporting

The NM_000350.3(ABCA4):​c.6320G>A​(p.Arg2107His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,614,112 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign 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. R2107P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (9 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21 U:1 O:2
• Conservation: PhyloP100: 7.85

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 11 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94001069-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 635988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 1-94001068-C-T is Pathogenic according to our data. Variant chr1-94001068-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94001068-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94001068-C-T is described in Lovd as [Likely_benign]. Variant chr1-94001068-C-T is described in Lovd as [Pathogenic]. Variant chr1-94001068-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.014489025). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00598 (911/152284) while in subpopulation AFR AF= 0.0208 (865/41574). AF 95% confidence interval is 0.0197. There are 8 homozygotes in gnomad4. There are 405 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.6320G>A	p.Arg2107His	missense_variant	Exon 46 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.6098G>A	p.Arg2033His	missense_variant	Exon 45 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.6320G>A	p.Arg2107His	missense_variant	Exon 46 of 50	1	NM_000350.3	ENSP00000359245.3

Frequencies

GnomAD3 genomes AF: 0.00598 AC: 910 AN: 152166 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00148 AC: 372 AN: 251290 Hom.: 3 AF XY: 0.00100 AC XY: 136 AN XY: 135820

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00103

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000645 AC: 943 AN: 1461828 Hom.: 9 Cov.: 33 AF XY: 0.000538 AC XY: 391 AN XY: 727208

Gnomad4 AFR exome AF: 0.0206

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00227

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.00598 AC: 911 AN: 152284 Hom.: 8 Cov.: 32 AF XY: 0.00544 AC XY: 405 AN XY: 74454

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00115 Hom.: 2

Bravo AF: 0.00674

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00187 AC: 227

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:21 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5 Uncertain:1 Other:2

Jun 02, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2107 of the ABCA4 protein (p.Arg2107His). This variant is present in population databases (rs62642564, gnomAD 2.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Stargardt disease and/or cone dystrophy (PMID: 9781034, 10458172, 19243736, 24011517, 25066811, 25283059, 28118664, 28446513, 28559085, 29925512, 30060493, 32307445, 32619608). 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: 99448). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). This variant disrupts the p.Arg2107 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11527935, 23755871, 24097981, 29310964, 29925512, 30718709). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ABCA4 p.Arg2107His variant accounts for up to 20% of pathogenic variants identified in Stargardt disease patients of African descent (Zernant 2014). This variant has also been identified in trans with other pathogenic alleles (selected references: Rozet 1998, Utz 2013, Jiang 2016, and Fujinami 2019). This variant is found in the African population with an allele frequency of 2% (519/ 24,958 alleles, including 4 homozygotes) in the Genome Aggregation Database. Despite its high population frequency and presence of homozygotes in population databases, only a small number of homozygous individuals with Stargardt disease have been reported in the literature suggesting that in the homozygous state this allele may result in a milder phenotype or reduced penetrance (Zernant 2014). Based on available information, this variant is considered to be likely pathogenic. -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA4: PM3:Very Strong, PM1, PM5, PM2:Supporting, PS3:Supporting, BS2 -

Mar 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Additional genotype/phenotype studies are needed to better establish the contribution of R2107H to disease; This variant is associated with the following publications: (PMID: 16123440, 23499370, 25444351, 26780318, 23982839, 28559085, 16917483, 11385708, 19230850, 14709597, 15223829, 25884411, 26214332, 26311262, 19365039, 23882696, 25066811, 24011517, 11384574, 25283059, 25910913, 19243736, 23953153, 9781034, 29555955, 30093795, 29925512, 32845050, 32581362, 22995991, 22025579, 33301772, 33691693, 34426522, 32619608, 33261146, 22264887, 34073554) -

Severe early-childhood-onset retinal dystrophy Pathogenic:7

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3_Moderate+PM3_VeryStrong+PP4 -

Jan 01, 2016

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1). Other variant at this amino acid residue has been classified as pathogenic(PM5, p.Arg2107Cys). REVEL score is 0.88 (PP3_mod) -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Retinal dystrophy Pathogenic:3

Jan 01, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 11, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCA4-related disorder Pathogenic:1

Mar 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCA4 c.6320G>A variant is predicted to result in the amino acid substitution p.Arg2107His. This variant has been reported many times to be causative for ABCA4-associated retinal disorders (see for example Rozet et al. 1998. PubMed ID: 9781034; Riveiro-Alvarez et al. 2009. PubMed ID: 18977788; Fujinami et al. 2018. PubMed ID: 29925512). This variant has been documented in 2.1% of alleles in individuals of African descent in gnomAD, including multiple homozygous individuals. While this allele frequency is higher than expected for most pathogenic variants, it has been reported that the carrier frequency for late-onset Stargardt disease is particularly high in the general population (Riveiro-Alvarez et al. 2009. PubMed ID: 18977788). Missense prediction programs classify this amino acid change as damaging, and multiple functional studies have confirmed that this variant has a mild hypomorphic effect on the protein (Sun et al. 2000. PubMed ID: 11017087; Curtis et al. 2020. PubMed ID: 32845050). Given the mild effect, the literature suggests that individuals who are homozygous for this variant have a very mild phenotype (Zernant et al. 2014. PubMed ID: 25066811). In summary, we interpret this variant as likely pathogenic. -

Optic atrophy Pathogenic:1

Jan 01, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macular dystrophy Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Retinitis pigmentosa 19 Pathogenic:1

Jan 09, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29493581). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17412879). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012602 /PMID: 16170316 /3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 16170316, 16443854, 16835863, 16881968, 17054105, 19669404). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16329078, 16372351, 16835863, 16969868, 18039947, 19206176, 19371735, 20660566). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Gly12Ala, p.Gly12Arg, p.Gly12Asp, p.Gly12Cys, p.Gly12Glu, p.Gly12Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012600, VCV000012603, VCV000012612, VCV000012613, VCV000040430, VCV000163690, VCV000180854, VCV000279921, VCV000375961, VCV001209208 /PMID: 16155195, 16170316, 16443854, 18039947, 22495892, 27195699, 28489335 /3billion dataset). 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

Jan 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt disease Pathogenic:1

Oct 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg2107His variant in ABCA4 has been reported in the compound heterozygous state in at least 19 individuals and in the homozygote state in an individual with clinical features of Stargardt disease. The homozygous individual had late-onset disease (Rozet 1998 PMID: 9781034, Utz 2013 PMID: 24011517, Zernant 2014 PMID: 25066811, Stone 2017 PMID: 28559085, Vallim Salles 2018 PMID: 30093795) and accounts for about 1/5 of pathogenic variants identified in affected individuals of African American descent (Zernant 2014 PMID: 25066811). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 99448) and has been identified in 2.1% (864/41452) of African chromosomes by gnomAD including 9 homozygotes (http://gnomad.broadinstitute.org, v.3.1.2), which is higher than the expected frequency for penetrant disease-causing alleles. However, very few homozygous individuals with Stargardt disease have been reported in the literature suggesting that in the homozygous state, this allele may result in a milder, subclinical phenotype or reduced penetrance. In vitro studies show that this variant showed slightly reduced expression in transfected cells and decreased ATPase activity but were still able to bind and be stimulated by trans-retinal (Curtis 2020 PMID: 32845050), which could be consistent with the milder phenotype observed in homozygotes and the later age of onset of disease. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Stargardt disease and is expected to cause more severe disease in the compound heterozygote state with a penetrant, more severe pathogenic variant on the other copy of the gene (in trans). ACMG/AMP Criteria applied: PM3_VeryStrong, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
MetaRNN	Benign	0.014	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.1	.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.026	D;D
Polyphen		1.0	.;D
Vest4		0.99
MVP		0.99
MPC		0.52
ClinPred		0.11	T
GERP RS		6.1
Varity_R		0.52
gMVP		0.87

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

Other links and lift over

dbSNP: rs62642564; hg19: chr1-94466624; COSMIC: COSV64672059; COSMIC: COSV64672059;