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

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Oct 25, 2021
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:: RCV000787514.17

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]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000221171	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (May 28, 2020)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9295268, 20696155, 22312191, 19074458, 22025579, 11017087, 16103129, 22661473, 19217903, 24033266
SCV000926482	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet - VeluxRD	no assertion criteria provided	Pathogenic (Apr 1, 2018)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001160823	Sharon lab, Hadassah-Hebrew University Medical Center	no assertion criteria provided	Pathogenic (Jun 23, 2019)	inherited	research
SCV001983384	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 25, 2021)	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	6	6	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

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

Loss of peripapillary sparing in non-group I Stargardt disease.

Burke TR, Allikmets R, Smith RT, Gouras P, Tsang SH.

Exp Eye Res. 2010 Nov;91(5):592-600. doi: 10.1016/j.exer.2010.07.018. Epub 2010 Aug 7.

PubMed [citation]

PMID:: 20696155
PMCID:: PMC2962723

See all PubMed Citations (12)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000221171.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (10)

Description

The p.Gly1961Glu (NM_000350.2 c.5882G>A) variant in ABCA4 has been reported >20 individuals with Stargardt disease and other retinal phenotypes and segregated with disease in 5 affected individuals from 5 families, but has been associated with reduced penetrance (Allikmets 1997 PMID:9295268, Burke 2012 PMID:22312191, Burke 2012 PMID:22661473, Song 2011 PMID:22025579, Burke 2010 PMID:20696155, Wiszniewski 2005 PMID:16103129, Cella 2009 PMID:19217903, Cideciyan 2009 PMID: 19074458). The variant shows a statistically significant (p<0.0001) difference in allele frequency in cases (5%) compared to the general population (0.4%, http://gnomad.broadinstitute.org). In vitro functional studies support an impact on protein function (Sun 2000 PMID:11017087). This variant has also been reported as Pathogenic by multiple clinical labs in ClinVar (Variation ID 7879). In summary, this variant meets criteria to be classified as pathogenic for Stargardt disease in an autosomal recessive manner, though it may show reduced penetrance and a milder clinical presentation compared to other pathogenic variants in the ABCA4 gene. ACMG/AMP Criteria applied: PS3_Supporting, PM3_VeryStrong, PP1_Strong.

#	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		6	not provided	6	not provided

From Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet - VeluxRD, SCV000926482.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)
2	not provided	not provided	not provided	not provided	research	PubMed (1)

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

From Sharon lab, Hadassah-Hebrew University Medical Center, SCV001160823.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

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

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001983384.2

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

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

Last Updated: Jun 9, 2024

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