NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp) AND not provided

Germline classification:: Pathogenic/Likely pathogenic; other (6 submissions)
Last evaluated:: Apr 1, 2024
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:: RCV000085683.25

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]

Observations:

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
SCV000117823	Retina International	no classification provided	not provided	not provided	not provided
SCV000321353	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Oct 4, 2018)	germline	clinical testing	Citation Link,
SCV000339315	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	other (Aug 31, 2017)	germline	clinical testing	Citation Link,
SCV001210838	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 14, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 9781034, 28041643, 28559085, 29925512, 11687513, 10711710, 11527935, 23755871, 26103963, 28118664, 28492532
SCV001447306	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004702745	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Apr 1, 2024)	germline	clinical testing	Citation Link

Description

http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_ABCR:c.4918C>T: SCV000117823

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	1	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies.

Rozet JM, Gerber S, Souied E, Perrault I, Châtelin S, Ghazi I, Leowski C, Dufier JL, Munnich A, Kaplan J.

Eur J Hum Genet. 1998 May-Jun;6(3):291-5. Erratum in: Eur J Hum Genet 1999 Jan;7(1):102.

PubMed [citation]

PMID:: 9781034

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, Megy K, Grozeva D, Dewhurst E, Malka S, Plagnol V, Penkett C, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, et al.

Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.

PubMed [citation]

PMID:: 28041643
PMCID:: PMC5223092

See all PubMed Citations (12)

Details of each submission

From Retina International, SCV000117823.1

#	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 GeneDx, SCV000321353.7

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

Description

The R1640W pathogenic variant in the ABCA4 gene has been reported previously in autosomal recessive Stargardt disease in affected individuals when in the homozgyous state or when in trans with another pathogenic variant (Battu et al., 2015; Fujinami et al., 2013; Rozet et al., 1998). The R1640W variant has been reported on the same allele (in cis) with the W1408R variant in families with Stargardt disease, and in a family presenting with both Stargardt disease and retinitis pigmentosa, when in trans with another pathogenic variant (Valverde et al, 2006; Shroyer et al, 2001). Shroyer et al. (2001) showed very little protein from cells transfected with the W1408R and R1640W variants in cis; however, proteins bearing only the W1408R or the R1640W variants appear to have mild or moderate defects in expression or stability. The R1640W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1640W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret R1640W as a pathogenic variant.

#	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 Eurofins Ntd Llc (ga), SCV000339315.4

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

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001210838.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1640 of the ABCA4 protein (p.Arg1640Trp). This variant is present in population databases (rs61751404, gnomAD 0.007%). This missense change has been observed in individuals with ABCA4-related conditions (PMID: 9781034, 28041643, 28559085, 29925512). ClinVar contains an entry for this variant (Variation ID: 99330). 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: 11687513). This variant disrupts the p.Arg1640 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10711710, 11527935, 23755871, 26103963, 28118664). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, SCV001447306.1

#	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 CeGaT Center for Human Genetics Tuebingen, SCV004702745.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

Description

ABCA4: PM3:Very Strong, PM2, PM5

#	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		3	not provided	not provided	not provided

Last Updated: Oct 26, 2024

Relating variation to medicine