NM_000350.3(ABCA4):c.6112C>T (p.Arg2038Trp) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 4, 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:: RCV000085789.11

Allele description [Variation Report for NM_000350.3(ABCA4):c.6112C>T (p.Arg2038Trp)]

NM_000350.3(ABCA4):c.6112C>T (p.Arg2038Trp)

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.6112C>T (p.Arg2038Trp)

HGVS:

NC_000001.11:g.94005476G>A
NG_009073.1:g.120674C>T
NG_009073.2:g.120672C>T
NM_000350.3:c.6112C>TMANE SELECT
NM_001425324.1:c.5890C>T
NP_000341.2:p.Arg2038Trp
NP_001412253.1:p.Arg1964Trp
NC_000001.10:g.94471032G>A
NM_000350.2:c.6112C>T
P78363:p.Arg2038Trp

Protein change:

R1964W

Links:

UniProtKB: P78363#VAR_008495; dbSNP: rs61750643

NCBI 1000 Genomes Browser:

rs61750643

Molecular consequence:

NM_000350.3:c.6112C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.5890C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000117931	Retina International	no classification provided	not provided	not provided	not provided
SCV001402865	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 4, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15161829, 24763286, 29854428, 29925512, 12962493, 28492532
SCV001447777	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001768476	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 21, 2022)	germline	clinical testing	Citation Link

Description

http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_ABCR:c.6112C>T: SCV000117931

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	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Mutation spectrum and founder chromosomes for the ABCA4 gene in South African patients with Stargardt disease.

September AV, Vorster AA, Ramesar RS, Greenberg LJ.

Invest Ophthalmol Vis Sci. 2004 Jun;45(6):1705-11.

PubMed [citation]

PMID:: 15161829

Molecular diagnosis of putative Stargardt disease by capture next generation sequencing.

Zhang X, Ge X, Shi W, Huang P, Min Q, Li M, Yu X, Wu Y, Zhao G, Tong Y, Jin ZB, Qu J, Gu F.

PLoS One. 2014;9(4):e95528. doi: 10.1371/journal.pone.0095528.

PubMed [citation]

PMID:: 24763286
PMCID:: PMC3999032

See all PubMed Citations (7)

Details of each submission

From Retina International, SCV000117931.1

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

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

From Invitae, SCV001402865.5

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2038 of the ABCA4 protein (p.Arg2038Trp). This variant is present in population databases (rs61750643, gnomAD 0.007%). This missense change has been observed in individuals with Stargardt disease (PMID: 15161829, 24763286, 29854428, 29925512). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99430). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 12962493). For these reasons, this variant has been classified as Pathogenic.

#	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		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447777.1

#	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	1	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001768476.3

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

Description

Published functional studies demonstrate that the p.(R2038W) variant results in decreased ATP hydrolysis and decreased binding affinity for ATP (Biswas-Fiss et al., 2003); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9054934, 11379881, 15161829, 24763286, 28118664, 31054281, 29555955, 29854428, 33261146, 33090715, 31510083, 22328824, 22863181, 19230850, 9973280, 30093795, 12962493, 29925512)

#	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: Mar 30, 2024

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Relating variation to medicine