chr1-94001992-C-G

Position:

chr1-94001992-C-G

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

Splicing: ADA: 0.9980

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]

ABCA4 links:

ABCA4 (HGNC:):

ABCA4 links:

Genome browser will be placed here

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
ABCA4	NM_000350.3 linkuse as main transcript	c.6148G>C	p.Val2050Leu	missense_variant, splice_region_variant	45/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.5926G>C	p.Val1976Leu	missense_variant, splice_region_variant	44/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.6148G>C	p.Val2050Leu	missense_variant, splice_region_variant	45/50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000465352.1 linkuse as main transcript	n.564G>C		splice_region_variant, non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes

AF:

0.00310

AC:

472

AN:

152144

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.00388

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00275

AC:

334

Asia WGS

AF:

0.000289

AC:

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 submitter	clinical testing	Revvity Omics, Revvity	Jul 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department 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 coneâ€šÃ„Ã¬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 submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ABCA4: BP2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2024	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) -

Severe early-childhood-onset retinal dystrophy

Pathogenic:3Uncertain:1

Likely pathogenic, flagged submission	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
Pathogenic, flagged submission	literature only	OMIM	Jul 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, flagged submission	research	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	-	- -

ABCA4-related disorder

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	Across 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 provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 10, 2024	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. -

Retinal dystrophy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 07, 2019	- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, flagged submission

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Cone dystrophy

Pathogenic:1

Likely pathogenic, flagged submission

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 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 submitter

clinical testing

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

Mar 07, 2022

- -

Stargardt disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cone-Rod Dystrophy, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 17, 2016

- -

Stargardt Disease, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Macular degeneration

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

0.17

.;N

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.50

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over