NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu) AND ABCA4-related disorder

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 18, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000273328.15

Allele description [Variation Report for NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)]

NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

Gene:

ABCA4:ATP binding cassette subfamily A member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p22.1

Genomic location:

Preferred name:

NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

HGVS:

NC_000001.11:g.94008251C>T
NG_009073.1:g.117899G>A
NG_009073.2:g.117897G>A
NM_000350.3:c.5882G>AMANE SELECT
NM_001425324.1:c.5660G>A
NP_000341.2:p.Gly1961Glu
NP_000341.2:p.Gly1961Glu
NP_001412253.1:p.Gly1887Glu
NC_000001.10:g.94473807C>T
NM_000350.2:c.5882G>A
P78363:p.Gly1961Glu

Protein change:

G1887E; GLY1961GLU

Links:

UniProtKB: P78363#VAR_008475; OMIM: 601691.0007; dbSNP: rs1800553

NCBI 1000 Genomes Browser:

rs1800553

Molecular consequence:

NM_000350.3:c.5882G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.5660G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: ABCA4-related disorder
Synonyms:: ABCA4-Related Disorders; ABCA4-related condition
Identifiers:: MedGen: CN239167

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000359235	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (May 8, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 11017087, 9295268, 16103129, 19217903, 23769331, 22661473, 22312191, 18285826, 26527198 Citation Link,
SCV002754519	Variantyx, Inc.	criteria provided, single submitter (Variantyx Assertion Criteria 2022)	Pathogenic (Nov 4, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 30060493, 29555955, 28559085, 19074458, 28181551, 25921964, 23755871, 26780318, 28118664 Citation Link,
SCV004109410	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000359235

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(May 8, 2017)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV002754519

Variantyx, Inc.

criteria provided, single submitter

(Variantyx Assertion Criteria 2022)

Pathogenic
(Nov 4, 2022)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV004109410

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 18, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Biochemical defects in ABCR protein variants associated with human retinopathies.

Sun H, Smallwood PM, Nathans J.

Nat Genet. 2000 Oct;26(2):242-6.

PubMed [citation]

PMID:: 11017087

Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration.

Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, Peiffer A, Zabriskie NA, Li Y, Hutchinson A, Dean M, Lupski JR, Leppert M.

Science. 1997 Sep 19;277(5333):1805-7.

PubMed [citation]

PMID:: 9295268

See all PubMed Citations (19)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000359235.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The ABCA4 c.5882G>A (p.Gly1961Glu) missense variant has been reported in at least eight studies in which it is found in over 50 individuals, 54 of whom were diagnosed with Stargardt disease, including 18 who carry the variant in a homozygous state, in at least 26 who carry the variant in a compound heterozygous state, and in seven who carry the variant in a heterozygous state. The p.Gly1961Glu variant is also found in a heterozygous state in two asymptomatic individuals (Allikmets et al. 1997; Wiszniewski et al. 2005; Kitiratschky et al. 2008; Cella et al. 2009; Burke et al. 2012; Burke et al. 2012; Fujinami et al. 2013; Lee et al. 2016). The p.Gly1961Glu variant is associated with a mild phenotype. Fifteen of the individuals carrying the variant exhibited bull's eye maculopathy and retinal dysfunction limited to the macula and not typical general dysfunction (Cella et al. 2009). Six individuals were found to carry additional variants in the ABCA4 gene and exhibited a more severe phenotype (Burke et al. 2012). The p.Gly1961Glu variant was absent from 220 control individuals and is reported at a frequency of 0.01498 in the South Asian population of the Exome Aggregation Consortium. Haplotype analysis in the South Asian population suggested that the p.Gly1961Glu variant has a founder effect in this population (Fujinami et al. 2013). Functional studies demonstrated that the p.Gly1961Glu variant protein resulted in reduced ATPase activity and ATP binding, while maintaining expression levels comparable to wild type, which is consistent with a mild phenotype. Additionally, the variant protein ATPase activity was inhibited by all-trans retinal, in contrast to the stimulation seen in wild type (Sun et al. 2000; Burke et al 2012a). Based on the collective evidence, the p.Gly1961Glu variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Variantyx, Inc., SCV002754519.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This is a nonsynonymous variant in the ABCA4 gene (OMIM 601691). Biallelic pathogenic variants in this gene have been associated with autosomal recessive ABCA4-related disorders. This variant has been reported in the homozygous or compound heterozygous state in many individuals with mild or late-onset ABCA4-related disease (PMID: 30060493, 29555955, 28559085, 19074458, 28181551) (PM3_Strong). Additionally, this variant has been shown to confer a moderate risk (~3-fold) for age-related macular degeneration (PMID: 25921964). Functional studies have shown that this variant alters ABCA4 protein function (PMID: 11017087, 29847635) (PS3). An alternate amino acid change at this position (p.Gly1961Arg) has been previously reported as pathogenic in affected individuals (PMID: 23755871, 19074458, 26780318, 28118664) (PM5). Multiple computational algorithms predict a deleterious effect for this amino acid substitution (PP3). This variant has a 1.378% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on current evidence, this variant is classified as pathogenic for autosomal recessive ABCA4-related disorders.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV004109410.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The ABCA4 c.5882G>A variant is predicted to result in the amino acid substitution p.Gly1961Glu. This variant has been reported many times in the compound heterozygous state in individuals with retinal dystrophy and has been associated with later-onset and milder retinal phenotypes (see for examples Cella et al. 2009. PubMed ID: 19217903, Lewis et al. 1999. PubMed ID: 9973280, Allikmets et al. 1997. PubMed ID: 9295268, Fujinami et al. 2013. PubMed ID: 23769331). This variant is documented with a global allele frequency of 0.46% in gnomAD, including several homozygotes (http://gnomad.broadinstitute.org/variant/1-94473807-C-T). This allele frequency is relatively high and consistent with this variant causing a more mild and later-onset retinal phenotype (Burke et al. 2012. PubMed ID: 22661473). However, when this variant is present in cis with other pathogenic ABCA4 variants as a complex allele, it has been reported to cause severe retinal phenotypes (Burke et al. 2012. PubMed ID: 22661473). Given the evidence, we interpret c.5882G>A (p.Gly1961Glu), both alone and as part of a complex allele, as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 26, 2024

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