NM_000350.3(ABCA4):c.5318C>T (p.Ala1773Val) AND Stargardt disease

Clinical significance:Pathogenic (Last evaluated: Jan 8, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:

Allele description [Variation Report for NM_000350.3(ABCA4):c.5318C>T (p.Ala1773Val)]

NM_000350.3(ABCA4):c.5318C>T (p.Ala1773Val)

ABCA4:ATP binding cassette subfamily A member 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000350.3(ABCA4):c.5318C>T (p.Ala1773Val)
  • NC_000001.11:g.94014685G>A
  • NG_009073.1:g.111465C>T
  • NM_000350.3:c.5318C>TMANE SELECT
  • NP_000341.2:p.Ala1773Val
  • NC_000001.10:g.94480241G>A
  • NM_000350.2:c.5318C>T
  • p.Ala1773Val
Protein change:
dbSNP: rs760549861
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000350.3:c.5318C>T - missense variant - [Sequence Ontology: SO:0001583]


Stargardt disease (FFM)
Stargardt's disease; Fundus flavimaculatus
MONDO: MONDO:0019353; MedGen: C0271093; Orphanet: 827

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000967649Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
(Jun 5, 2018)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001160831Sharon lab,Hadassah-Hebrew University Medical Centerno assertion criteria providedLikely pathogenic
(Jun 23, 2019)

SCV001337920Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
(Jan 8, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedinheritedyesnot providednot providednot providednot providednot providedresearch



Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy.

Duncker T, Tsang SH, Lee W, Zernant J, Allikmets R, Delori FC, Sparrow JR.

Ophthalmology. 2015 Feb;122(2):345-55. doi: 10.1016/j.ophtha.2014.08.017. Epub 2014 Oct 3.

PubMed [citation]

Detection rate of pathogenic mutations in ABCA4 using direct sequencing: clinical and research implications.

Downes SM, Packham E, Cranston T, Clouston P, Seller A, NĂ©meth AH.

Arch Ophthalmol. 2012 Nov;130(11):1486-90. doi: 10.1001/archophthalmol.2012.1697. No abstract available.

PubMed [citation]
See all PubMed Citations (8)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000967649.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (7)


The p.Ala1773Val variant in ABCA4 has been reported in >10 individuals with Star gardt disease and/or retinal degeneration, including at least 3 compound heteroz ygotes and 6 homozygotes, and segregated in 4 affected relatives (Stenirri 2008, Chacon-Camacho 2013, Duncker 2015, Biswas 2017, Lopez-Rubio 2018). This variant has been reported in ClinVar (Variation ID: 236129) and has been identified in 0.05% (16/33582) of Latino chromosomes by the Genome Aggregation Database (gnomA D, http://gnomad.broadinstitute.org/; dbSNP rs760549861). Although this variant is seen in the general population, its frequency is consistent with a recessive carrier frequency. Additionally, another allele the same position (p.Ala1773Glu) has been reported with a similar phenotype (Downes 2012), suggesting that chang es at this position may not be tolerated. In summary, this variant is pathogenic for Stargardt disease in an autosomal recessive manner. ACMG/AMP Criteria appli ed: PM3_VeryStrong; PP1_Moderate; PP3.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Sharon lab,Hadassah-Hebrew University Medical Center, SCV001160831.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001337920.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)


Variant summary: ABCA4 c.5318C>T (p.Ala1773Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251426 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ABCA4 causing Stargardt disease (7.6e-05 vs 0.0014), allowing no conclusion about variant significance. c.5318C>T has been reported in the literature in numerous individuals affected with Stargardt disease (homozygotes and heterozygotes) and may be a Mexican founder mutation (Chacon-Camacho_2013, Fujinami_2019, Lopez-Rubio_2018, Stenirri_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Oct 6, 2021

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