NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp) AND Severe early-childhood-onset retinal dystrophy

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Mar 30, 2023
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:: RCV000408519.11

Allele description [Variation Report for NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp)]

NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp)

Genes:

ABCA4:ATP binding cassette subfamily A member 4 [Gene - OMIM - HGNC]
LOC126805793:CDK7 strongly-dependent group 2 enhancer GRCh37_chr1:94486302-94487501 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

1p22.1

Genomic location:

Preferred name:

NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp)

Other names:

NP_000341.2:p.(Arg1640Trp)

HGVS:

NC_000001.11:g.94021340G>A
NG_009073.1:g.104810C>T
NG_009073.2:g.104808C>T
NG_082117.1:g.695G>A
NM_000350.3:c.4918C>TMANE SELECT
NM_001425324.1:c.4696C>T
NP_000341.2:p.Arg1640Trp
NP_001412253.1:p.Arg1566Trp
NC_000001.10:g.94486896G>A
NM_000350.2:c.4918C>T
P78363:p.Arg1640Trp

Protein change:

R1566W

Links:

UniProtKB: P78363#VAR_008461; dbSNP: rs61751404

NCBI 1000 Genomes Browser:

rs61751404

Molecular consequence:

NM_000350.3:c.4918C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.4696C>T - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001573564	Ocular Genomics Institute, Massachusetts Eye and Ear	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 8, 2021)	germline	research	PubMed (14) [See all records that cite these PMIDs] 30718709, 29925512, 28559085, 28118664, 28041643, 26872967, 26103963, 25082885, 23755871, 11687513, 11527935, 10711710, 9781034, 25741868
SCV002503642	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9781034, 10090887, 11687513, 21873672, 25741868
SCV002558011	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 23769331, 25066811, 25922843, 29854428, 30060493, 30834176, 31522899, 31766579, 25741868
SCV005047039	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	no assertion criteria provided	Pathogenic	germline	research	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, research

Citations

PubMed

Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.

Jespersgaard C, Fang M, Bertelsen M, Dang X, Jensen H, Chen Y, Bech N, Dai L, Rosenberg T, Zhang J, Møller LB, Tümer Z, Brøndum-Nielsen K, Grønskov K.

Sci Rep. 2019 Feb 4;9(1):1219. doi: 10.1038/s41598-018-38007-2.

PubMed [citation]

PMID:: 30718709
PMCID:: PMC6362094

Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.

Fujinami K, Strauss RW, Chiang JP, Audo IS, Bernstein PS, Birch DG, Bomotti SM, Cideciyan AV, Ervin AM, Marino MJ, Sahel JA, Mohand-Said S, Sunness JS, Traboulsi EI, West S, Wojciechowski R, Zrenner E, Michaelides M, Scholl HPN; ProgStar Study Group.; ProgStar Study Group..

Br J Ophthalmol. 2019 Mar;103(3):390-397. doi: 10.1136/bjophthalmol-2018-312064. Epub 2018 Jun 20.

PubMed [citation]

PMID:: 29925512
PMCID:: PMC6579578

See all PubMed Citations (24)

Details of each submission

From Ocular Genomics Institute, Massachusetts Eye and Ear, SCV001573564.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (14)

Description

The ABCA4 c.4918C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PM1, PM3-S. Based on this evidence we have classified this variant as Pathogenic.

#	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

From Molecular Genetics, Royal Melbourne Hospital, SCV002503642.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change is predicted to replace arginine with tryptophan at codon 1640 of the ABCA4 protein, p.(Arg1640Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and there is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.003%, consistent with recessive disease (rs61751404, 8/251,420 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in the homozygous state and compound heterozygous with a second pathogenic allele in multiple Stargardt disease cases (PMID: 9781034, 10090887, 11687513, 21873672). The missense change causes reduced protein expression and ATPase activity in in vitro functional assays (PMID: 11687513). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). A different missense change at the same amino acid residue (p.Arg1640Gln) determined to be pathogenic has been seen before (ClinVar ID: 99331). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PM2, PM5, PS3_Supporting, PP3.

#	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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002558011.2

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200), cone-rod dystrophy 3 (MIM#604116), fundus flavimaculatus (MIM#248200), early-onset severe retinal dystrophy (MIM#248200) and retinitis pigmentosa 19 (MIM#601718). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (8 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (8 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC2_membrane_3 domain (Protein DataBank). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals diagnosed with Stargardt disease (ClinVar, PMIDs: 23769331, 25066811, 25922843, 29854428, 30060493, 30834176, 31766579). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

From Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana, SCV005047039.1

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

Last Updated: Oct 26, 2024

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