NM_000350.3(ABCA4):c.2819C>G (p.Pro940Arg) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Oct 18, 2022
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:: RCV000316390.12

Allele description [Variation Report for NM_000350.3(ABCA4):c.2819C>G (p.Pro940Arg)]

NM_000350.3(ABCA4):c.2819C>G (p.Pro940Arg)

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.2819C>G (p.Pro940Arg)

HGVS:

NC_000001.11:g.94047018G>C
NG_009073.1:g.79132C>G
NG_009073.2:g.79130C>G
NM_000350.3:c.2819C>GMANE SELECT
NM_001425324.1:c.2597C>G
NP_000341.2:p.Pro940Arg
NP_001412253.1:p.Pro866Arg
NC_000001.10:g.94512574G>C
NM_000350.2:c.2819C>G

Protein change:

P866R

Links:

dbSNP: rs144995371

NCBI 1000 Genomes Browser:

rs144995371

Molecular consequence:

NM_000350.3:c.2819C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.2597C>G - 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
SCV000340406	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Mar 17, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10634626, 11919200, 18024811, 23144455 Citation Link,
SCV001420818	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 18, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10634626, 18024811, 30060493, 11919200, 23144455, 28492532
SCV001919060	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001971322	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing

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	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

ABCR gene analysis in familial exudative age-related macular degeneration.

Souied EH, Ducroq D, Rozet JM, Gerber S, Perrault I, Munnich A, Coscas G, Soubrane G, Kaplan J.

Invest Ophthalmol Vis Sci. 2000 Jan;41(1):244-7.

PubMed [citation]

PMID:: 10634626

ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy.

Michaelides M, Chen LL, Brantley MA Jr, Andorf JL, Isaak EM, Jenkins SA, Holder GE, Bird AC, Stone EM, Webster AR.

Br J Ophthalmol. 2007 Dec;91(12):1650-5.

PubMed [citation]

PMID:: 18024811
PMCID:: PMC2095527

See all PubMed Citations (6)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000340406.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

#	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, SCV001420818.4

#	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 proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 940 of the ABCA4 protein (p.Pro940Arg). This variant is present in population databases (rs144995371, gnomAD 0.06%). This missense change has been observed in individual(s) with macular degeneration and/or Stargardt disease (PMID: 10634626, 18024811, 30060493; Invitae). ClinVar contains an entry for this variant (Variation ID: 286835). 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 not expected to disrupt ABCA4 protein function. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11919200, 23144455). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001919060.1

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001971322.1

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

Last Updated: Nov 18, 2024

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