1-94098944-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBS1_SupportingBS2

The NM_000350.3(ABCA4):c.618C>G(p.Ser206Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000861 in 1,612,628 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S206S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0046 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 4 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:2O:1

Conservation

PhyloP100: 0.125

Publications

14 publications found

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 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

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.009199023).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00455 (693/152300) while in subpopulation AFR AF = 0.0159 (661/41564). AF 95% confidence interval is 0.0149. There are 6 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.618C>G	p.Ser206Arg	missense_variant	Exon 6 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1 link	c.618C>G	p.Ser206Arg	missense_variant	Exon 6 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.618C>G	p.Ser206Arg	missense_variant	Exon 6 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1 link	c.618C>G	p.Ser206Arg	missense_variant	Exon 6 of 19			ENSP00000496882.1

Frequencies

GnomAD3 genomes

AF:

0.00455

AC:

693

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00107

AC:

266

AN:

249070

AF XY:

0.000757

show subpopulations

Gnomad AFR exome

AF:

0.0154

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000477

AC:

696

AN:

1460328

Hom.:

Cov.:

AF XY:

0.000423

AC XY:

307

AN XY:

726400

show subpopulations

African (AFR)

AF:

0.0177

AC:

593

AN:

33478

American (AMR)

AF:

0.000492

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51908

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111992

Other (OTH)

AF:

0.00103

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00455

AC:

693

AN:

152300

Hom.:

Cov.:

AF XY:

0.00443

AC XY:

330

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0159

AC:

661

AN:

41564

American (AMR)

AF:

0.00137

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000244

Hom.:

Bravo

AF:

0.00527

ExAC

AF:

0.00134

AC:

163

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:1Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 31, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant has also been observed in individuals with retinal dystrophy who had other disease-causing ABCA4 variants or variants in another gene that may have also contributed to the phenotype (PMID: 10206579, 24265693); Published functional studies demonstrate a damaging effect with reduced ATPase activity compared to wild type (PMID: 11017087); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22995991, 24265693, 17982420, 20647261, 32531858, 35456422, 36284670, 11017087, 10206579, 11328725, 11846518, 32307445, 35120629, 38219857) -

ABCA4-related disorder

Uncertain:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jul 15, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ABCA4 c.618C>G variant is predicted to result in the amino acid substitution p.Ser206Arg. This variant has been reported along with a second ABCA4 variant in individuals with retinal disease (Birch et al. 2001. PubMed ID: 11846518; Table S1, Schindler et al. 2010. PubMed ID: 20647261; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858; Table S2, Zhu et al. 2022. PubMed ID: 35456422). However, this variant has also been reported as an additional allele in an individual with retinal disease explained by variants in the RDH12 gene (Eisenberger et al. 2013. PubMed ID: 24265693). Functional studies have shown that the p.Ser206Arg substitution decreases protein activity (Sun et al. 2000. PubMed ID: 11017087). This variant is reported in 1.5% of alleles in individuals of African descent in gnomAD, including 10 homozygous individuals in the v4.1.0 dataset (https://gnomad.broadinstitute.org/variant/1-94098944-G-C?dataset=gnomad_r4). This variant has conflicting classifications in ClinVar ranging from pathogenic to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/99434/). Given the conflicting evidence at this time, the clinical significance of this variant is uncertain. -

not specified

Uncertain:1Benign:1

Apr 19, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 12, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ABCA4 c.618C>G (p.Ser206Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 280464 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency near the estimated frequency for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.0014 vs 0.0014). However, the variant is observed at a higher frequency in control chromosomes in the African population (10-fold above the estimated frequency for a pathogenic variant), providing conflicting evidence about variant significance. c.618C>G has been reported in the literature in individuals affected with Retinitis Pigmentosa, Stargardt disease, and other inherited retinal disorders (examples: Fishman_1999, Birch_2001, Webster_2001, Weisschuh_2020, Eisenberger_2013, Zhu_2022) both in the absence and presence of second variants with a range of pathogenicity, many with unknown pathogenicity. These data do not allow any conclusion about variant significance. In experimental studies, the variant was reported to have reduced basal ATPase activity and little stimulation by retinal (Sun_2000). The following publications have been ascertained in the context of this evaluation (PMID: 11846518, 10206579, 11328725, 32531858, 11017087, 24265693, 36284670). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic (n=1), VUS (n=3), benign (n=2)). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19

Uncertain:1

Aug 14, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Severe early-childhood-onset retinal dystrophy

Uncertain:1

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1

Jun 11, 2020

Blueprint Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

D;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.83

T;D

MetaRNN

Benign

0.0092

T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

0.13

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.4

N;.

REVEL

Pathogenic

0.73

Sift

Benign

0.13

T;.

Sift4G

Benign

0.23

T;.

Polyphen

1.0

D;.

Vest4

0.74

MutPred

0.82

Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);

MVP

0.91

MPC

0.35

ClinPred

0.13

GERP RS

-4.1

Varity_R

0.18

gMVP

0.84

Mutation Taster

=47/53

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over