NM_000350.3:c.1622T>C

Variant names:

• chr1-94063250-A-G
• rs61751392
• NM_000350.3:c.1622T>C

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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:29 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 rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.1622T>C	p.Leu541Pro	missense_variant	Exon 12 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.1622T>C	p.Leu541Pro	missense_variant	Exon 12 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.1622T>C	p.Leu541Pro	missense_variant	Exon 12 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.1622T>C	p.Leu541Pro	missense_variant	Exon 12 of 19			ENSP00000496882.1

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:29 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy Pathogenic:9

Jan 31, 2023

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 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 -

Jan 03, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 08, 2019

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS1,PS3,PP2,PP3,PP5 -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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. -

Dec 11, 2023

North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Mod PM3_Str PP3_Mod PS3_Str -

Aug 11, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:6 Uncertain:1 Other:1

Mar 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, PM2, PP3, PS3:Supporting -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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, 25712131, 29847635). For these reasons, this variant has been classified as Pathogenic. -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (PMID: 11017087, 16103129, 25712131); 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: 37510321, 37498587, 35120629, 35260635, 31964843, 36460718, 32307445, 36672815, 29701254, 33749171, 34321860, 34906470, 9781034, 28118664, 29847635, 38003421, 37734845, 31429209, 32531858, 19217903, 19074458, 24713488, 24509150, 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, 10958763, 22312191, 23918662) -

Sep 22, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Nov 16, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:4

Aug 07, 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

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 24, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt disease Pathogenic:3

Aug 14, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Macular dystrophy Pathogenic:2

Nov 22, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Retinitis pigmentosa Pathogenic:2

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Pathogenic:1

Mar 04, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 23, 2018

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,PP2,PP3. -

ABCA4-related disorder Pathogenic:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.
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;