NM_000350.3:c.6148G>C

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

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

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA4: BP2, BS1, BS2

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.

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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.

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 26, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 17, 2025

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 suggests 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, 31736247, 37958660, 35120629, 30060493, 28041643, 23755871, 36969552, 36010202, 36209838, 10880298, 20335603, 39162841, 38219857, 39384610, 39693084, 39087934, 33258285, 32307445, 34996991)

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

Jul 07, 2023

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

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

Mar 07, 2019

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2023

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

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

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
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	0.0	.;N
PhyloP100		7.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.0	.;N
Sift	Pathogenic	0.0	.;T
Sift4G	Benign	0.063	T;T
Vest4		0.78
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;