rs41292677

Variant names:

• chr1-94001992-C-G
• rs41292677
• NM_000350.3:c.6148G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1 PP2 PP3 BP6 BS2

The NM_000350.3(ABCA4):​c.6148G>C​(p.Val2050Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,614,142 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (11 hom.)
• Consequence: ABCA4 NM_000350.3 missense, splice_region
• Scores: Splicing: ADA: 0.9980
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:10 B:7 O:1
• Conservation: PhyloP100: 7.45
• Publications: 58 publications found

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]

ABCA4 Gene-Disease associations (from GenCC):

• ABCA4-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa 19

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Stargardt disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 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, 7 uncertain in NM_000350.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 578 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: -0.65813 (below the threshold of 3.09). Trascript score misZ: 1.3628 (below the threshold of 3.09). GenCC associations: The gene is linked to cone-rod dystrophy 3, retinitis pigmentosa 19, ABCA4-related retinopathy, severe early-childhood-onset retinal dystrophy, cone-rod dystrophy, Stargardt disease, retinitis pigmentosa.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 1-94001992-C-G is Benign according to our data. Variant chr1-94001992-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7884.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.6148G>C	p.Val2050Leu	missense_variant, splice_region_variant	Exon 45 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.5926G>C	p.Val1976Leu	missense_variant, splice_region_variant	Exon 44 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.6148G>C	p.Val2050Leu	missense_variant, splice_region_variant	Exon 45 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000465352.1	n.564G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 6	5

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152144 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00297 AC: 746 AN: 251450 AF XY: 0.00274

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00587

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00370 AC: 5414 AN: 1461880 Hom.: 11 Cov.: 32 AF XY: 0.00350 AC XY: 2546 AN XY: 727240

African (AFR) AF: 0.000896 AC: 30 AN: 33480

American (AMR) AF: 0.00615 AC: 275 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00585 AC: 153 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00424 AC: 4714 AN: 1112004

Other (OTH) AF: 0.00373 AC: 225 AN: 60396

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152262 Hom.: 2 Cov.: 33 AF XY: 0.00302 AC XY: 225 AN XY: 74452

African (AFR) AF: 0.000770 AC: 32 AN: 41552

American (AMR) AF: 0.00843 AC: 129 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00393 AC: 267 AN: 68014

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00356 Hom.: 0

Bravo AF: 0.00388

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00275 AC: 334

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00498

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:10 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:2 Other:1

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Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 26, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA4: BP2 -

Jan 10, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in patients with Stargardt disease and retinal dystrophy in the presence of another ABCA4 variant, but also in the heterozygous state in individuals with a pathogenic variant in another gene explaining their phenotype (PMID: 23940504, 25698705, 28118664, 28061825, 29555955, 29884405, 29925512, 30718709); Observed in the homozygous state in a patient with macular dystrophy in the literature (PMID: 31736247); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 1137988, 22427542, 31429209, 32531858, 25698705, 9054934, 9666097, 16103129, 23953153, 15494742, 11726554, 9973280, 11527935, 18285826, 28224992, 26593885, 34426522, 33546218, 12796258, 28118664, 25884411, 28061825, 10913642, 29555955, 28492530, 11328725, 28341476, 30190494, 30798147, 29884405, 28157192, 30653986, 30718709, 31212395, 30670881, 31980526, 32581362, 32619608, 32783370, 23940504, 29925512, 33633436, 35836572, 34327195, 34996991, 31736247, 37958660, 35120629, 30060493, 28041643, 23755871, 36969552, 36010202, 36209838, 10880298, 20335603) -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ABCA4 c.6148G>C; p.Val2050Leu variant (rs41292677) is reported in the literature in multiple individuals affected with Stargardt disease, retinitis pigmentosa, or a related retinal disorder (Allikmets 1997, Corton 2013, Haer-Wigman 2017, Sciezynska 2016, Wiszniewski 2005). This variant has been observed in trans to a pathogenic variant in affected individuals (Corton 2013); however, it has also been observed in cis to a nonsense variant in at least one study (Sciezynska 2016). The p.Val2050Leu variant is found in the Latino population with an overall allele frequency of 0.60% (211/35438 alleles) in the Genome Aggregation Database and is reported with conflicting classifications in ClinVar (Variation ID: 7884). The leucine at codon 2050 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the p.Val2050Leu variant is uncertain at this time. References: Allikmets R et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997 Mar;15(3):236-46. Corton M et al. Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis. PLoS One. 2013 Jun 14;8(6):e65574. Haer-Wigman L et al. Diagnostic exome sequencing in 266 Dutch patients with visual impairment. Eur J Hum Genet. 2017 May;25(5):591-599. Sciezynska A et al. Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe. Exp Eye Res. 2016 Apr;145:93-99. 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. -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCA4 p.Val2050Leu variant was identified in 13 of 2830 proband chromosomes (frequency: 0.00459) from individuals or families with inherited retinal diseases including macular dystrophy, cone-rod dystrophy and Stargardt disease (Haer-Wigman_2017_PMID:28224992; Carss_2017_PMID:28041643; Schulz_2017_PMID:28118664; Sciezynska_2016_PMID:26593885). A study of a family with macular dystrophy, cone dystrophy, and cone–rod dystrophy in five-generations identified variants in the PRPH2, ABCA4, and ROM1 genes; family members heterozygous for only the ABCA4 V2050L variant showed mildly reduced macular function with centrally reduced mfERG amplitudes and additional minor fundus abnormalities (Poloschek_2010_PMID:20335603). The V2050L variant was identified in dbSNP (ID: rs41292677), ClinVar (classified as benign 1x, likely benign 4x, VUS 2x, likely pathogenic 2x and pathogenic 1x) and LOVD 3.0 (classified as a VUS and likely pathogenic). The variant was also identified in control databases in 808 of 282834 chromosomes (1 homozygous) at a frequency of 0.002857 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 211 of 35438 chromosomes (freq: 0.005954), Ashkenazi Jewish in 50 of 10368 chromosomes (freq: 0.004823), Other in 29 of 7226 chromosomes (freq: 0.004013), European (non-Finnish) in 500 of 129166 chromosomes (freq: 0.003871), African in 13 of 24950 chromosomes (freq: 0.000521) and European (Finnish) in 5 of 25118 chromosomes (freq: 0.000199); it was not observed in the East Asian or South Asian populations. The p.Val2050 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Val2050Leu variant occurs in the first base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, only 2 of 4 in silico or computational prediction software programs (MaxEntScan, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Severe early-childhood-onset retinal dystrophy Pathogenic:3 Uncertain:1

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Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

Jul 07, 2023

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Uncertain:2

Jan 01, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2019

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: flagged submission

Collection Method: research

- -

Cone 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

- -

ABCA4-related disorder Uncertain:1

Sep 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCA4 c.6148G>C variant is predicted to result in the amino acid substitution p.Val2050Leu. This variant has been reported in several large cohort studies of retinal disease; however, often times a second ABCA4 variant was not detected (see for examples: Corton et al. 2013. PubMed ID: 23940504; Wiszniewski et al. 2005. PubMed ID: 16103129; Poloschek et al. 2010. PubMed ID: 20335603; Table S1, Lin et al. 2024. PubMed ID: 38219857 ). This variant is reported in 0.60% of alleles in individuals of Latino descent in gnomAD, including several homozygous individuals in the latest dataset (https://gnomad.broadinstitute.org/variant/1-94001992-C-G?dataset=gnomad_r4). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Uncertain:1

Mar 07, 2022

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt disease Uncertain:1

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

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 VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ABCA4-related eye disease (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) 0200 - Variant is predicted to result in a missense amino acid change from valine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (468 heterozygotes, 2 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ABC transporter domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as benign, likely benign, likely pathogenic and as a VUS six times in ClinVar (most recently benign and VUS). It has been reported as a homozygous variant in at least one patient with macular dystrophy with no additional data (PMID: 31736247) and in trans with another pathogenic missense variant in a retinitis pigmentosa family however segregation data was inconclusive (PMID: 25698705). This variant has also been reported as a heterozygous variant in multiple patients with ABCA4-related eye disease, where a 2nd disease-causing variant was not determined (PMID 22427542; 23755871; 30190494; 30718709). In addition, this variant has been identified as a complex allele with unknown zygosity in at least 2 families (PMID: 32783370; 30060493). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Retinitis Pigmentosa, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Cone-Rod Dystrophy, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 17, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt Disease, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macular degeneration Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.17	.;N
PhyloP100		7.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	.;N
REVEL	Pathogenic	0.76
Sift	Benign	0.069	.;T
Sift4G	Benign	0.063	T;T
Polyphen		0.95	.;P
Vest4		0.78
MVP		0.90
MPC		0.46
ClinPred		0.047	T
GERP RS		5.7
Varity_R		0.52
gMVP		0.89
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs41292677; hg19: chr1-94467548;