rs61748550

chr1-94079339-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000350.3(ABCA4):c.1222C>T(p.Arg408Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,972 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ABCA4 NM_000350.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 0.129

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]

LOC124904222 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-94079339-G-A is Pathogenic according to our data. Variant chr1-94079339-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 99035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94079339-G-A is described in Lovd as [Pathogenic]. Variant chr1-94079339-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94079339-G-A is described in Lovd as [Pathogenic]. Variant chr1-94079339-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.1222C>T	p.Arg408Ter	stop_gained	9/50	ENST00000370225.4
LOC124904222	XR_007066231.1	n.203-4390G>A		intron_variant, non_coding_transcript_variant
ABCA4	XM_047416704.1	c.1222C>T	p.Arg408Ter	stop_gained	9/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.1222C>T	p.Arg408Ter	stop_gained	9/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.1222C>T	p.Arg408Ter	stop_gained	9/19

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251456 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.0000275 AC XY: 20 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74294

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000406 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 26, 2017	- -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Arg408*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs61748550, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Stargardt disease or retinitis pigmentosa (PMID: 16103129, 23755871). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99035). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23953153, 25525159, 28947085, 30771335, 16103129, 11846518, 23755871, 14709597, 11328725, 28118664, 23891399, 30060493, 33369172, 33301772, 32619608) -

Severe early-childhood-onset retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 01, 2016

- -

Retinitis pigmentosa 19 Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 25, 2023

The heterozygous p.Arg408Ter variant in ABCA4 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 99288) and a known risk variant (ClinVar Variation ID: 99390), in one individual with retinal dystrophy. This individual also carried another pathogenic variant (ClinVar Variation ID: 99288) and a known risk variant (ClinVar Variation ID: 99390); however, the phase of these variants is unknown at this time. The p.Arg408Ter variant in ABCA4 has been previously reported in 13 unrelated individuals with autosomal recessive ABCA4-related retinopathy (PMID: 30771335, PMID: 14709597, PMID: 30060493, PMID: 33369172, PMID: 33301772, PMID: 32619608, PMID: 16103129, PMID: 23755871, PMID: 11846518) and segregated with disease in 2 affected relatives from one family (PMID: 16103129), but has been identified in 0.005% (1/19952) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs61748550). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 13 affected individuals (PMID: 30771335, PMID: 14709597, PMID: 30060493, PMID: 33369172, PMID: 33301772, PMID: 32619608, PMID: 16103129, PMID: 23755871, PMID: 11846518), 7 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 23755871, ClinVar Variation ID: 99224, 99283; PMID: 16103129, ClinVar Variation ID: 99084; PMID: 32619608, ClinVar Variation ID: 1065650; PMID: 33301772, ClinVar Variation ID: 99208; PMID: 33369172, ClinVar Variation ID: 854791; PMID: 30771335, ClinVar Variation ID: 7879), one was a compound heterozygote who carried a likely pathogenic variant with unknown phase (PMID: 11846518, ClinVar Variation ID: 99307), and 4 were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 32619608, ClinVar Variation ID: 7888, 99265; PMID: 33301772; PMID: 30060493, ClinVar Variation ID: 866940), which increases the likelihood that the p.Arg408Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 99035) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 408, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive ABCA4-related retinopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ABCA4-related retinopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong (Richards 2015). -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 11, 2019

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 28, 2023

Variant summary: ABCA4 c.1222C>T (p.Arg408X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251456 control chromosomes. c.1222C>T has been reported in the literature in multiple individuals affected with Stargardt disease (e.g. Riveiro-Alvarez_2013) or other ABCA4-related retinopathy. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23755871). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.16	N
MutationTaster	Benign	1.0	A;A
Vest4		0.90
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs61748550; hg19: chr1-94544895; COSMIC: COSV64673562;