rs61751392

chr1-94063250-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_000350.3(ABCA4):c.1622T>C(p.Leu541Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,614,014 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. L541P?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 U:1 O:1
• Conservation: PhyloP100: 8.95

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 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94063249-TA-TGG is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 1-94063250-A-G is Pathogenic according to our data. Variant chr1-94063250-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94063250-A-G is described in Lovd as [Pathogenic]. Variant chr1-94063250-A-G is described in Lovd as [Likely_pathogenic]. Variant chr1-94063250-A-G is described in Lovd as [Likely_benign]. Variant chr1-94063250-A-G is described in Lovd as [Likely_pathogenic]. Variant chr1-94063250-A-G is described in Lovd as [Pathogenic]. Variant chr1-94063250-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.1622T>C	p.Leu541Pro	missense_variant	12/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.1622T>C	p.Leu541Pro	missense_variant	12/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.1622T>C	p.Leu541Pro	missense_variant	12/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.1622T>C	p.Leu541Pro	missense_variant	12/19

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152146 Hom.: 0 Cov.: 32

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: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251410 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135872

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: 0.000647

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 185 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.000154 AC XY: 112 AN XY: 727234

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: 0.00

Gnomad4 FIN exome AF: 0.000599

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74322

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: 0.000660

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000265 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 11, 2022	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The ABCA4 c.1622T>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: PS3, PM2, PM3, PP3, PP5. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 31, 2023	This variant was identified together with NM_000350.3:c.3113C>T, NM_000350.3:c.2588G>C, NM_000350.3:c.5693G>A and NM_000350.3:c.1411G>A. Criteria applied: PM3_VSTR, PS3_MOD, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Jan 08, 2019	ACMG categories: PS1,PS3,PP2,PP3,PP5 -
Likely 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: VCV000099067, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.983, 3CNET: 0.996, PP3_P). A missense variant is a common mechanism associated with Stargardt disease 1 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000163, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:5 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2023	Functional studies demonstrate that the p.(L541P)/p.(A1038V) complex allele as well as the p.(L541P) and p.(A1038V) variants independently result in reduced ATPase activity; however, the affect of p.(A1038V) is milder compared to that of p.(L541P) alone or the p.(L541P)/p.(A1038V) complex allele (Sun et al., 2000; Wiszniewski et al., 2005; Zhang et al., 2015); 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: 9781034, 28118664, 29847635, 31429209, 32531858, 19217903, 19074458, 24713488, 24509150, 10958763, 25712131, 10958761, 11328725, 26593885, 28041643, 16103129, 29555955, 29186038, 29068140, 30204727, 29925512, 30718709, 30653986, 32581362, 31573552, 33851411, 32619608, 32783370, 32037395, 32141364, 30643219, 33369172, 29114839, 28559085, 31456290, 35836572, 35119454, 34315337, 11017087, 11527935) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ABCA4: PM3:Very Strong, PM1, PM2, PP3, PS3:Supporting -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 541 of the ABCA4 protein (p.Leu541Pro). This variant is present in population databases (rs61751392, gnomAD 0.07%). This missense change has been observed in individuals with Stargardt disease, cone-rod dystrophy, or retinitis pigmentosa (PMID: 10206579, 11527935, 16103129, 19217903, 23755871, 24509150, 26593885, 28041643). ClinVar contains an entry for this variant (Variation ID: 99067). 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, 25712131, 29847635). 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	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 22, 2023	- -

Retinal dystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 07, 2019	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Stargardt disease Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 14, 2018	The p.Leu541Pro variant in ABCA4 has been reported in the compound heterozygous state in >4 individuals with Stargardt disease or related retinal dystrophy and as a part of the Leu541Pro/Ala1038Val complex allele (in cis with p.Ala1038Val) in >25 compound heterozygous or homozygous individuals with Stargardt disease or related retinal dystrophy (Rozet 1998, Rivera 2000, Webster 2001, Briggs 2001, Gerth 2002, Hargitai 2005, Cideciyan 2009, Braun 2013, Fujinami 2013, Bertelse n 2014, Audere 2015, Fakin 2016, Lee 2016, Carss 2017, Porto 2017, Salles 2017) . The p.Leu541Pro variant segregated with disease in 1 compound heterozygous sib ling (Lee 2016), and the Leu541Pro/Ala1038Val complex allele segregated with dis ease in >12 affected relatives (Rivera 2000, Wiszniewski 2005, Braun 2013, Sall es 2017). The p.Leu541Pro variant has been identified in 0.07% (17/25792) of Fin nish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs61751392) and has also been reported in ClinVar (Variatio n ID: 99067). A mouse model of the complex allele resulted in a Stargardt-like p henotype in homozygous mice (Zhang 2015). Additional functional studies demonstr ated that the p.Leu541Pro and p.A1038V alleles each impact functional activity a nd that the Leu541Pro/Ala1038Val complex allele is more severe, resembling a com plete loss of activity (Sun 2000, Wiszniewski 2005, Zhang 2015). In summary, the p.Leu541Pro variant meets criteria to be classified as pathogenic for Stargardt disease in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VerySt rong; PS3_Supporting; PP3. -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Macular dystrophy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 22, 2021	This variant was identified aspotentially compound heterozygous with NM_000350.3:c.3113C>T and NM_000350.3:c.5882G>A. Criteria applied: PM3_VSTR, PS3_MOD, PP3 -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Retinitis pigmentosa Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 04, 2019

The ABCA4 c.1622T>C; p.Leu541Pro variant (rs61751392), is reported in the literature in numerous individuals affected with Stargardt disease, retinitis pigmentosa, or other related retinopathies (Briggs 2001, Rivera 2000, Rozet 1998, Wiszniewski 2005). This variant is commonly reported in cis to another missense variant, p.Ala1038Val, and the [p.Leu541Pro; p.Ala1038Val] complex variant has been reported in the homozygous and compound heterozygous states in multiple affected individuals (Briggs 2001, Rivera 2000, Wiszniewski 2005). Functional studies suggest that p.Leu541Pro, independent of p.Ala1038Val, causes protein misfolding, mislocalization, and reduced ATP binding and hydrolysis (Sun 2000, Wiszniewski 2005, Zhang 2015). The p.Leu541Pro variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 99067) and is found in the general population with an overall allele frequency of 0.02% (46/282812 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Briggs CE et al. Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2229-36. Rivera A et al. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet. 2000 Oct;67(4):800-13. Rozet JM et al. Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies. Eur J Hum Genet. 1998 May-Jun;6(3):291-5. Sun H et al. Biochemical defects in ABCR protein variants associated with human retinopathies. Nat Genet. 2000 Oct;26(2):242-6. Wiszniewski W et al. ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies. Hum Mol Genet. 2005 Oct 1;14(19):2769-78. Zhang N et al. Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations. Hum Mol Genet. 2015 Jun 1;24(11):3220-37. -

Age related macular degeneration 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 23, 2018

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3. -

ABCA4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

The ABCA4 c.1622T>C variant is predicted to result in the amino acid substitution p.Leu541Pro. This variant has been reported as causative for autosomal recessive Stargardt Disease (STGD) (see for example Rozet et al. 1998. PubMed ID: 9781034; Wiszniewski et al. 2005. PubMed ID: 16103129). This variant is frequently detected on the same chromosome (in cis) with another ABCA4 variant, c.3113C>T (p.Ala1038Val), as the complex allele p.[Leu541Pro;Ala1038Val] in patients with autosomal recessive retinal dystrophy (Burke et al. 2012. PubMed ID: 22312191; Cella et al. 2009. PubMed ID: 19217903; Wiszniewski et al. 2005. PubMed ID: 16103129; Klevering et al. 2004. PubMed ID: 15494742). The complex allele is reported to cause a more severe phenotype than either variant individually (Zhang et al. 2015. PubMed ID: 25712131). This variant is reported in 0.068% of alleles in individuals of European (Finnish) descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99067/). Given all the evidence, we interpret c.1622T>C (p.Leu541Pro) both alone and as part of the complex allele p.[Leu541Pro;Ala1038Val] as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Uncertain	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0070	D;.
Polyphen		0.99	D;.
Vest4		0.96
MVP		1.0
MPC		0.58
ClinPred		0.88	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.98

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: rs61751392; hg19: chr1-94528806;