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NM_000350.3(ABCA4):c.4297G>A (p.Val1433Ile) AND ABCA4-related disorder

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Apr 27, 2017
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000778256.15

Allele description [Variation Report for NM_000350.3(ABCA4):c.4297G>A (p.Val1433Ile)]

NM_000350.3(ABCA4):c.4297G>A (p.Val1433Ile)

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.4297G>A (p.Val1433Ile)
HGVS:
  • NC_000001.11:g.94030483C>T
  • NG_009073.1:g.95667G>A
  • NG_009073.2:g.95665G>A
  • NM_000350.3:c.4297G>AMANE SELECT
  • NM_001425324.1:c.4075G>A
  • NP_000341.2:p.Val1433Ile
  • NP_001412253.1:p.Val1359Ile
  • NC_000001.10:g.94496039C>T
  • NM_000350.2:c.4297G>A
  • P78363:p.Val1433Ile
Protein change:
V1359I
Links:
UniProtKB: P78363#VAR_008449; dbSNP: rs56357060
NCBI 1000 Genomes Browser:
rs56357060
Molecular consequence:
  • NM_000350.3:c.4297G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001425324.1:c.4075G>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000914428Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)		Uncertain significance
(Apr 27, 2017) 		germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

Citation Link,

SCV005367123PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Uncertain significance
(Aug 11, 2024) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

An analysis of allelic variation in the ABCA4 gene.

Webster AR, Héon E, Lotery AJ, Vandenburgh K, Casavant TL, Oh KT, Beck G, Fishman GA, Lam BL, Levin A, Heckenlively JR, Jacobson SG, Weleber RG, Sheffield VC, Stone EM.

Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89.

PubMed [citation]
PMID:
11328725

High-throughput retina-array for screening 93 genes involved in inherited retinal dystrophy.

Song J, Smaoui N, Ayyagari R, Stiles D, Benhamed S, MacDonald IM, Daiger SP, Tumminia SJ, Hejtmancik F, Wang X.

Invest Ophthalmol Vis Sci. 2011 Nov 25;52(12):9053-60. doi: 10.1167/iovs.11-7978.

PubMed [citation]
PMID:
22025579
PMCID:
PMC3231844
See all PubMed Citations (14)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000914428.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (14)

Description

The ABCA4 c.4297G>A (p.Val1433Ile) missense variant has been reported in 14 studies in individuals with a range of ocular disorders (Lewis et al. 1999; Souied et al. 2000; Webster et al. 2001; Baum et al. 2003; Klevering et al. 2004; Valverde et al. 2007; Michaelides et al. 2007; Aguirre-Lamban et al. 2009; Kellner et al. 2009; Passerini et al. 2010; Song et al. 2011; Verdina et al. 2012; Huang et al. 2014; Grassmann et al. 2015). The p.Val1433Ile variant was found in a homozygous state in two individuals with Stargardt disease (STGD), in a compound heterozygous state in one individual with STGD and one with retinal degeneration. The variant was further reported in a complex compound heterozygous state in a patient with recessive cone-rod dystrophy (CRD), and in a heterozygous state in four patients with recessive CRD, three patients with age-related macular degeneration (AMD), and one patient each with STGD and bull’s eye maculopathy. Segregation analysis in one AMD family revealed that the variant did not segregate with disease. The variant was found in a heterozygous state in two of 484 controls and is reported at a frequency of 0.00441 in the Other population of the Exome Aggregation Consortium. Additionally, one homozygote is reported in the European (non-Finnish) population of the Exome Aggregation Consortium. Despite the evidence of causality, the discordant reports of lack of co-segregation of the variant with disease and the presence of an ostensibly healthy homozygote in the frequency databases present conflicting support for pathogenicity. The p.Val1433Ile variant is therefore 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From PreventionGenetics, part of Exact Sciences, SCV005367123.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ABCA4 c.4297G>A variant is predicted to result in the amino acid substitution p.Val1433Ile. This variant has been reported in the heterozygous state alone or with a second ABCA4 variant in individuals with Stargardt disease and cone-rod dystrophy (for example, see Lewis et al. 1999. PubMed: 9973280; Thiadens et al. 2012. PubMed: 22264887; Taylor et al. 2017. PubMed ID: 28341476; Del Pozo-Valero et al. 2022. PubMed ID: 35119454). Of note, this variant has also been detected in an individual who also had a potential causative variant in the PROM1 gene (associated with a retinal disorder) (Song et al. 2011. PubMed: 22025579). However, this variant is reported in 0.25% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including in several homozygous individuals in the latest gnomAD dataset (https://gnomad.broadinstitute.org/variant/1-94030483-C-T?dataset=gnomad_r4), which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 10, 2024