VCV000286835.17 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 286835 Accession: VCV000286835.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94047018 (GRCh38) [ NCBI UCSC ] 1: 94512574 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Feb 7, 2023	Oct 18, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.2819C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Pro940Arg	missense
NM_001425324.1:c.2597C>G	NP_001412253.1:p.Pro866Arg	missense
NC_000001.11:g.94047018G>C
NC_000001.10:g.94512574G>C
NG_009073.1:g.79132C>G
NG_009073.2:g.79130C>G

... more HGVS ... less HGVS

Protein change

P940R, P866R

Other names

Canonical SPDI

NC_000001.11:94047017:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00024

Trans-Omics for Precision Medicine (TOPMed) 0.00025

The Genome Aggregation Database (gnomAD), exomes 0.00026

The Genome Aggregation Database (gnomAD) 0.00034

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038

Links

ClinGen: CA958146 dbSNP: rs144995371 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ABCA4		-	-	GRCh38 GRCh37	3759	4113

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Oct 18, 2022	RCV000316390.12
Retinal dystrophy	Uncertain significance (1)	criteria provided, single submitter	Sep 1, 2017	RCV001075267.2
ABCA4-related disorder	Uncertain significance (1)	criteria provided, single submitter	Jan 30, 2018	RCV001101951.4
Age related macular degeneration 2 Cone-rod dystrophy 3 Retinitis pigmentosa 19 Severe early-childhood-onset retinal dystrophy	Uncertain significance (1)	criteria provided, single submitter	Sep 22, 2021	RCV002487242.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 17, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000340406.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (4) PubMed: 10634626‚ 11919200‚ 18024811‚ 23144455 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Sep 01, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240882.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Uncertain significance (Jan 30, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	ABCA4-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001258595.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (5) PubMed: 18024811‚ 10634626‚ 16533065‚ 23144455‚ 11919200 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Sep 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Age related macular degeneration 2 Severe early-childhood-onset retinal dystrophy Retinitis pigmentosa 19 Cone-rod dystrophy 3 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002777616.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Oct 18, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001420818.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	Publications: PubMed (5) PubMed: 10634626‚ 18024811‚ 30060493‚ 11919200‚ 23144455 Comment: 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). … (more) 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. (less)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001919060.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971322.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort.	Nassisi M	International journal of molecular sciences	2018	PMID: 30060493
Retinoid binding properties of nucleotide binding domain 1 of the Stargardt disease-associated ATP binding cassette (ABC) transporter, ABCA4.	Biswas-Fiss EE	The Journal of biological chemistry	2012	PMID: 23144455
ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy.	Michaelides M	The British journal of ophthalmology	2007	PMID: 18024811
Interaction of the nucleotide binding domains and regulation of the ATPase activity of the human retina specific ABC transporter, ABCR.	Biswas-Fiss EE	Biochemistry	2006	PMID: 16533065
Biochemical defects in retina-specific human ATP binding cassette transporter nucleotide binding domain 1 mutants associated with macular degeneration.	Suárez T	The Journal of biological chemistry	2002	PMID: 11919200
ABCR gene analysis in familial exudative age-related macular degeneration.	Souied EH	Investigative ophthalmology & visual science	2000	PMID: 10634626
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4	-	-	-	-

Text-mined citations for rs144995371 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs144995371 ...