rs41292677

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM5BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2050A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0037 ( 11 hom. )

Consequence

ABCA4
NM_000350.3 missense, splice_region

Scores

3
8
8
Splicing: ADA: 0.9980
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:11B:7O:1

Conservation

PhyloP100: 7.45
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000350.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-94001991-A-G is described in Lovd as [Likely_pathogenic].
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABCA4NM_000350.3 linkuse as main transcriptc.6148G>C p.Val2050Leu missense_variant, splice_region_variant 45/50 ENST00000370225.4 NP_000341.2 P78363Q6AI28
ABCA4XM_047416704.1 linkuse as main transcriptc.5926G>C p.Val1976Leu missense_variant, splice_region_variant 44/49

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ABCA4ENST00000370225.4 linkuse as main transcriptc.6148G>C p.Val2050Leu missense_variant, splice_region_variant 45/501 NM_000350.3 ENSP00000359245.3 P78363
ABCA4ENST00000465352.1 linkuse as main transcriptn.564G>C splice_region_variant, non_coding_transcript_exon_variant 6/65

Frequencies

GnomAD3 genomes
AF:
0.00310
AC:
472
AN:
152144
Hom.:
2
Cov.:
33
show subpopulations
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
GnomAD3 exomes
AF:
0.00297
AC:
746
AN:
251450
Hom.:
1
AF XY:
0.00274
AC XY:
372
AN XY:
135900
show subpopulations
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 SAS 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
show subpopulations
Gnomad4 AFR exome
AF:
0.000896
Gnomad4 AMR exome
AF:
0.00615
Gnomad4 ASJ exome
AF:
0.00585
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.000225
Gnomad4 NFE exome
AF:
0.00424
Gnomad4 OTH exome
AF:
0.00373
GnomAD4 genome
AF:
0.00310
AC:
472
AN:
152262
Hom.:
2
Cov.:
33
AF XY:
0.00302
AC XY:
225
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.000770
Gnomad4 AMR
AF:
0.00843
Gnomad4 ASJ
AF:
0.00634
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.00393
Gnomad4 OTH
AF:
0.00899
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:5Uncertain:11Benign:7Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4Benign:2Other:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJul 26, 2021- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
not provided, no classification providedliterature onlyRetina International-- -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023The 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. -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2024ABCA4: BP2 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 10, 2024Observed 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) -
Severe early-childhood-onset retinal dystrophy Pathogenic:3Uncertain:1
Likely pathogenic, flagged submissionclinical testingInstitute of Medical Molecular Genetics, University of ZurichJan 30, 2021- -
Pathogenic, flagged submissionliterature onlyOMIMJul 07, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Likely pathogenic, flagged submissionresearchOphthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana-- -
ABCA4-related disorder Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 05, 2019Across a selection of available literature, the ABCA4 c.6148G>C (p.Val2050Leu) missense variant has been reported in at least seven individuals affected with Stargardt macular degeneration including in three in a compound heterozygous state, in one in a heterozygous state and in at least three with unknown zygosity. The variant has also been reported in two brothers affected with cone-rod dystrophy in a compound heterozygous state with a frameshift variant on the second allele, and in a heterozygous state in one individual affected with macular dystrophy (Allikmets et al. 1997; Lewis et al. 1999; Corton et al. 2013; Schulz et al. 2017; Haer-Wigman et al. 2017). The variant failed to segregate with the disorder in one family affected with autosomal recessive retinitis pigmentosa and in one with autosomal dominant macular dystrophy (Wiszniewski et al. 2005; Poloschek et al. 2010). The p.Val2050Leu variant has also been found as a complex allele in cis with either a stop-gained variant or a missense variant in individuals affected with ABCA4-related disorders (Sciezynska et al. 2016; Schulz et al. 2017). The variant was found in a heterozygous state in one of 1528 control individuals and in one unaffected parent (Allikmets et al. 1997; Lewis et al. 1999; Corton et al. 2013; Sciezynska et al. 2016). This variant is reported at a frequency of 0.028846 in Puerto Ricans from Puerto Rico from the 1000 Genomes Project and in one homozygote in the European (non-Finnish) population of the Genome Aggregation Database. Poloschek et al. (2010) showed that, upon ophthalmic examination, heterozygous carriers of the p.Val2050Leu variant display centrally reduced mfERG amplitudes and additional minor fundus abnormalities, suggesting that the p.Val2050Leu variant is capable of mildly reducing macular function in the heterozygous state without an additional pathogenic variant on the second allele. Based on the collective evidence the p.Val2050Leu variant is classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 10, 2024The 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. -
Retinal dystrophy Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingBlueprint GeneticsMar 07, 2019- -
Retinitis pigmentosa Pathogenic:1
Pathogenic, flagged submissionresearchDepartment of Clinical Genetics, Copenhagen University Hospital, RigshospitaletApr 01, 2018- -
Cone dystrophy Pathogenic:1
Likely pathogenic, flagged submissionresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital BonnMar 07, 2022- -
Stargardt disease Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 06, 2021Based 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
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Cone-Rod Dystrophy, Recessive Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 17, 2016- -
Stargardt Disease, Recessive Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Macular degeneration Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

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
MutationTaster
Benign
1.0
A;A;A
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

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.84
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41292677; hg19: chr1-94467548; API