1-94060733-A-C

Position:

• chr1-94060733-A-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PP3 PP5_Very_Strong

The NM_000350.3(ABCA4):​c.1964T>G​(p.Phe655Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.27

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000350.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759
• PP5: Variant 1-94060733-A-C is Pathogenic according to our data. Variant chr1-94060733-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94060733-A-C is described in Lovd as [Likely_pathogenic]. Variant chr1-94060733-A-C is described in Lovd as [Pathogenic]. Variant chr1-94060733-A-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.1964T>G	p.Phe655Cys	missense_variant	14/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.1964T>G	p.Phe655Cys	missense_variant	14/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.1964T>G	p.Phe655Cys	missense_variant	14/50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.1964T>G	p.Phe655Cys	missense_variant	14/19			ENSP00000496882.1
ABCA4	ENST00000472033.1	n.84T>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000380 AC: 95 AN: 249696 Hom.: 0 AF XY: 0.000371 AC XY: 50 AN XY: 134874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000879

Gnomad NFE exome AF: 0.000612

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000297 AC: 434 AN: 1461266 Hom.: 0 Cov.: 32 AF XY: 0.000294 AC XY: 214 AN XY: 726852

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000918

Gnomad4 NFE exome AF: 0.000327

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000377 AC XY: 28 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000297 Hom.: 0

Bravo AF: 0.000317

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000552 AC: 67

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The ABCA4 c.1964T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3-S. Based on this evidence we have classified this variant as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2016	- -
Likely pathogenic, 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 likely pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease (MIM #248200), fundus flavimaculatus (MIM #248200), early-onset severe retinal dystrophy (MIM #248200) and retinitis pigmentosa 19 (MIM #601718). (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 phenylalanine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (110 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC2 membrane 3 domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as likely pathogenic and pathogenic four times in ClinVar in association with ABCA4-related eye disease. It has been reported in at least 10 patients with Stargardt or ABCA4-related eye disease in the literature where a 2nd disease-causing variant was identified in trans (PMIDs: 32821503; 22661472; 29925512; 28118664; 28446513; 21911583; 17296903; 31212395). This variant has also been reported as likely benign (based on case/control frequency data)/VUS (based on ACMG classification guidelines) by the same study (PMID: 28044389). (SP) 0705 - No comparable missene variants have previous evidence for pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 11, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2023	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: 17296903, 28118664, 22229821, 31589614, 22661472, 21911583, 29754767, 32619608, 33851411, 29925512, 34954332, 34874912, 32531858, 35119454) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 655 of the ABCA4 protein (p.Phe655Cys). This variant is present in population databases (rs200692438, gnomAD 0.09%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 21911583, 22229821, 22661472, 29925512). 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: 212727). 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. -

Retinal dystrophy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 09, 2019	- -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Oct 01, 2014

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.2	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		0.66	P;.
Vest4		0.87
MVP		0.97
MPC		0.55
ClinPred		0.67	D
GERP RS		5.9
Varity_R		0.85
gMVP		0.91

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: rs200692438; hg19: chr1-94526289;