chr1-94113062-C-T

Variant names:

• chr1-94113062-C-T
• rs62645958
• NM_000350.3:c.71G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PM5 PP2 PP5_Very_Strong BP4

The NM_000350.3(ABCA4):​c.71G>A​(p.Arg24His) variant causes a missense change. The variant allele was found at a frequency of 0.0000669 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 5.00

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]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94113063-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 severe early-childhood-onset retinal dystrophy, ABCA4-related retinopathy, cone-rod dystrophy 3, Stargardt disease, retinitis pigmentosa 19, cone-rod dystrophy, retinitis pigmentosa.
• PP5: Variant 1-94113062-C-T is Pathogenic according to our data. Variant chr1-94113062-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94113062-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94113062-C-T is described in Lovd as [Pathogenic]. Variant chr1-94113062-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94113062-C-T is described in Lovd as [Likely_benign].
• BP4: Computational evidence support a benign effect (MetaRNN=0.17898306). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.71G>A	p.Arg24His	missense_variant	Exon 2 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.71G>A	p.Arg24His	missense_variant	Exon 2 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.71G>A	p.Arg24His	missense_variant	Exon 2 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.71G>A	p.Arg24His	missense_variant	Exon 2 of 19			ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000179 AC: 45 AN: 250860 AF XY: 0.000147

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461704 Hom.: 0 Cov.: 34 AF XY: 0.0000646 AC XY: 47 AN XY: 727154

Gnomad4 AFR exome AF: 0.000179 AC: 6 AN: 33472

Gnomad4 AMR exome AF: 0.0000671 AC: 3 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26134

Gnomad4 EAS exome AF: 0.000554 AC: 22 AN: 39696

Gnomad4 SAS exome AF: 0.000209 AC: 18 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53370

Gnomad4 NFE exome AF: 0.0000234 AC: 26 AN: 1111900

Gnomad4 Remaining exome AF: 0.000315 AC: 19 AN: 60384

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74362

Gnomad4 AFR AF: 0.0000723 AC: 0.0000723066 AN: 0.0000723066

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00135 AC: 0.00135397 AN: 0.00135397

Gnomad4 SAS AF: 0.000208 AC: 0.000207555 AN: 0.000207555

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000294109 AN: 0.0000294109

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

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Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 10, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23419329, 11726554, 27820952, 34426522, 29162642, 31180159, 31015497, 9973280, 33261146, 31980526, 32307445, 36672815, 38219857, 23953153, 38540785, 36335097, 38984108, 35120629, 31429209, 33301772, 33608557, 38066771) -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 24 of the ABCA4 protein (p.Arg24His). This variant is present in population databases (rs62645958, gnomAD 0.1%). This missense change has been observed in individuals with retinopathy (PMID: 9973280, 27820952, 31015497). ClinVar contains an entry for this variant (Variation ID: 99498). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg24 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15494742, 28559085, 29162642, 30093795). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 30, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:2

Jan 01, 2016

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCA4-related disorder Pathogenic:1

Jul 31, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of literature, the ABCA4 c.71G>A (p.Arg24His) missense variant has been reported in a compound heterozygous state in five individuals with Stargardt disease (STGD) as well as in a heterozygous state in one individual (also with STGD) where a second variant was not identified (Lewis et al., 1999; Fujinami et al., 2013; Chacón-Camacho et al., 2013). Four of the compound heterozygous individuals belong to the same family and demonstrated segregation of the disease phenotype with the p.Arg24His variant. The p.Arg24His variant was absent from 440 control chromosomes and is reported at a frequency of 0.002091 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg24His variant is classified as likely pathogenic 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 Pathogenic:1

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1) + Homozygous allele count is less than 0 in gnomAD exomes and genomes (PM2). Other variant at this amino acid residue has been classified as pathogenic (PM5, p.Arg24Gly). REVEL score 0.811 (PP3_mod) -

Retinitis pigmentosa 19 Pathogenic:1

Dec 19, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.018%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.81 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000099498 /PMID: 9973280)and different missense changes at the same codon (p.Arg24Cys, p.Arg24Gly / ClinVar ID: VCV000099497, VCV000857107 / PMID: 15494742) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 9973280). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Pathogenic:1

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PM3_Strong+PP1_Moderate+PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.017	D;.
Sift4G	Uncertain	0.012	D;.
Polyphen		1.0	D;.
Vest4		0.92
MVP		0.97
MPC		0.52
ClinPred		0.19	T
GERP RS		5.0
Varity_R		0.20
gMVP		0.79
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62645958; hg19: chr1-94578618; COSMIC: COSV64670948;