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NM_000350.3(ABCA4):c.1761-2A>G AND Severe early-childhood-onset retinal dystrophy

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 30, 2023
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:
RCV002225134.2

Allele description [Variation Report for NM_000350.3(ABCA4):c.1761-2A>G]

NM_000350.3(ABCA4):c.1761-2A>G

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.1761-2A>G
HGVS:
  • NC_000001.11:g.94062755T>C
  • NG_009073.2:g.63393A>G
  • NM_000350.3:c.1761-2A>GMANE SELECT
  • NC_000001.10:g.94528311T>C
  • NG_009073.1:g.63395A>G
  • NM_000350.2:c.1761-2A>G
Links:
dbSNP: rs754765164
NCBI 1000 Genomes Browser:
rs754765164
Molecular consequence:
  • NM_000350.3:c.1761-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:
Severe early-childhood-onset retinal dystrophy (STGD1)
Synonyms:
MACULAR DYSTROPHY WITH FLECKS, TYPE 1; STGD; Stargardt macular dystrophy; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009549; MeSH: D000080362; MedGen: C1855465; Orphanet: 827; OMIM: 248200

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002503675Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Mar 30, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV002503675.2

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

Description

This sequence change affects an acceptor splice site in intron 13 of ABCA4. It is expected to disrupt RNA splicing and likely results in exon 13 skipping, which would likely disrupt the protein product by removing 59 amino acids in the first extracellular domain. Loss of function is a well established mechanism of disease (PVS1_Moderate). The variant is present in a large population cohort at a frequency of 0.0008%, which is consistent with recessive disease (rs754765164, 2/249,438 alleles, 0 homozygotes in gnomAD v2.1.1 - PM2). It has been identified as homozygous in a retinitis pigmentosa case (DOI: 10.3760/cma.j.issn.1674-845X.2016.03.005), and is confirmed compound heterozygous with a pathogenic missense variant (p.Arg602Trp) in a Stargardt disease patient in this laboratory (PM3). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Moderate, PM2, PM3.

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

Last Updated: Sep 29, 2024