rs138157885

Positions:

• chr1-94077722-G-A
• chr1-94077722-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM5 PP5

The NM_000350.3(ABCA4):​c.1522C>T​(p.Arg508Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000178 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R508H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5
• Conservation: PhyloP100: 3.75

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94077721-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3249758.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 1-94077722-G-A is Pathogenic according to our data. Variant chr1-94077722-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298258.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Pathogenic=2, Likely_pathogenic=1}. Variant chr1-94077722-G-A is described in Lovd as [Pathogenic]. Variant chr1-94077722-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94077722-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.1522C>T	p.Arg508Cys	missense_variant	11/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.1522C>T	p.Arg508Cys	missense_variant	11/49
LOC124904222	XR_007066231.1	n.203-6007G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.1522C>T	p.Arg508Cys	missense_variant	11/50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.1522C>T	p.Arg508Cys	missense_variant	11/19			ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251082 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135686

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000185 AC: 271 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 137 AN XY: 727060

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74464

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinal dystrophy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 13, 2017	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 508 of the ABCA4 protein (p.Arg508Cys). This variant is present in population databases (rs138157885, gnomAD 0.03%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 26780318, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 298258). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 31, 2023

Variant summary: ABCA4 c.1522C>T (p.Arg508Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251082 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.00018 vs 0.0014), allowing no conclusion about variant significance. c.1522C>T has been reported in the literature in multiple individuals affected with macular dystrophy (Michaelides_2007), autosomal recessive stargardt Disease (examples: Jiang_2015, Stone_2017, Hu_ABCA4_2019), cone-rod dystrophy (Jiang_2015, Falsini_2022), autosomal recessive retinitis pigmentosa (examples: Ma_2021, Neveling_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35260635, 31543898, 26780318, 33691693, 18024811, 22334370, 28559085). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic for autosomal recessive stargardt disease and retinitis pigmentosa. -

Retinitis Pigmentosa, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

ABCA4-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The ABCA4 c.1522C>T (p.Arg508Cys) missense variant has been reported in two studies in which it is found in a total of three individuals. The variant was found in a compound heterozygous state in one individual with Stargardt disease and another with cone-rod dystrophy and in a state of unknown zygosity in one individual with macular dystrophy (Michaelides et al. 2007; Jiang et al. 2016). The p.Arg508Cys variant was absent from 100 controls and is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Arg508Cys 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. -

Severe early-childhood-onset retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

DBGen Ocular Genomics

May 31, 2021

- -

Macular degeneration Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

The c.1522C>T (p.Arg508Cys) variant has been reported in two studies and is found in a total of three patients with various phenotypes including one in a compound heterozygous state with Stargardt disease, one in a compound heterozygous state with cone-rod dystrophy and one with macular dystrophy without clear zygosity information (Michaelides et al. 2007; Jiang et al. 2016). The p.Arg508Cys variant was absent from 100 controls and is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Arg508Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.66
Sift	Benign	0.041	D;.
Sift4G	Uncertain	0.029	D;.
Polyphen		0.92	P;.
Vest4		0.71
MVP		0.96
MPC		0.32
ClinPred		0.20	T
GERP RS		4.3
Varity_R		0.20
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs138157885; hg19: chr1-94543278; COSMIC: COSV64676760;