VCV000099070.19 - ClinVar

NM_000350.3(ABCA4):c.1648G>A (p.Gly550Arg)

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.

(11)

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.

Pathogenic/Likely pathogenic

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.1648G>A (p.Gly550Arg)

Variation ID: 99070 Accession: VCV000099070.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94063224 (GRCh38) [ NCBI UCSC ] 1: 94528780 (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	Feb 20, 2014	Jun 9, 2024	Dec 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.1648G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Gly550Arg	missense
NM_001425324.1:c.1648G>A	NP_001412253.1:p.Gly550Arg	missense
NC_000001.11:g.94063224C>T
NC_000001.10:g.94528780C>T
NG_009073.1:g.62926G>A
NG_009073.2:g.62924G>A
	P78363:p.Gly550Arg

... more HGVS ... less HGVS

Protein change

G550R

Other names

Canonical SPDI

NC_000001.11:94063223:C:T

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA226915 UniProtKB: P78363#VAR_012521 dbSNP: rs61748558 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	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 14, 2023	RCV000085413.12
ABCA4-related disorder	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 14, 2023	RCV000778263.5
Cone-rod dystrophy 3	Pathogenic (1)	criteria provided, single submitter	Mar 15, 2019	RCV000782281.2
Stargardt disease 3	Pathogenic (1)	no assertion criteria provided	-	RCV004558302.1
Retinitis pigmentosa 19	Likely pathogenic (1)	criteria provided, single submitter	Aug 21, 2017	RCV000761253.1
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jul 23, 2019	RCV001074836.2
Age related macular degeneration 2 Cone-rod dystrophy 3 Retinitis pigmentosa 19 Severe early-childhood-onset retinal dystrophy	Likely pathogenic (1)	criteria provided, single submitter	Mar 1, 2022	RCV000763048.3

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.
Pathogenic (Jul 23, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240436.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446892.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Cone-rod dystrophy (present) Sex: female
Likely pathogenic (Mar 01, 2022)	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: SCV000893529.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Nov 10, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321338.9 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24713488, 17982420, 22229821, 28559085, 30093795, 31589614, 33732702, 22264887, 24317291, 32619608, 31968401, 11726554, 11527935, 15192030, 33090715, 29925512) (less)
Pathogenic (Dec 14, 2023)	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: SCV001401167.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 11726554‚ 28559085‚ 29925512 Comment: This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 550 of the ABCA4 protein (p.Gly550Arg). … (more) This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 550 of the ABCA4 protein (p.Gly550Arg). This variant is present in population databases (rs61748558, gnomAD 0.003%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 11726554, 28559085, 29925512). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99070). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Aug 21, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 19 Affected status: yes Allele origin: germline	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota Accession: SCV000891210.1 First in ClinVar: Mar 24, 2019 Last updated: Mar 24, 2019	Publications: PubMed (1) PubMed: 11726554 Number of individuals with the variant: 1
Likely pathogenic (Oct 25, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	ABCA4-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914435.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (7) PubMed: 24713488‚ 11726554‚ 11527935‚ 15192030‚ 22264887‚ 25312043‚ 30093795 Comment: The ABCA4 c.1648G>A (p.Gly550Arg) missense variant has been identified in at least seven studies in which it is found in a total of seven individuals … (more) The ABCA4 c.1648G>A (p.Gly550Arg) missense variant has been identified in at least seven studies in which it is found in a total of seven individuals including in three in a compound heterozygous state with a known pathogenic variant and four in a heterozygous state with an undetected second allele (Shroyer et al., 2001; Briggs et al., 2001; Stenirri et al., 2004; Thiadens et al 2012; Bertelsen et al. 2014; Fujinami et al., 2015; Salles et al. 2018). Six of these individuals exhibited Stargardt disease and the seventh exhibited generalized choriocapillaris dystrophy. The p.Gly550Arg variant was absent from 100 control chromosomes (Shroyer et al., 2001) and is reported at a frequency of 0.00006 in the South Asian population of the Exome Aggregation Consortium, but this is based on one allele, so the variant is presumed to be rare. Based on the evidence, the p.Gly550Arg variant is classified as likely pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Mar 15, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cone-rod dystrophy 3 (Autosomal recessive inheritance) Affected status: no, yes Allele origin: germline	The Cell Therapy Center, The University of Jordan Accession: SCV000920582.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019	Comment: This variant was classified as pathogenic based on its segregation with the disease, allele frequency, and in-silico tools. One patient with this variant was found … (more) This variant was classified as pathogenic based on its segregation with the disease, allele frequency, and in-silico tools. One patient with this variant was found to have sectoral RP features. (less) Observation 1: Number of individuals with the variant: 2 Clinical Features: Sectoral retinitis pigmentosa (present) Sex: male Ethnicity/Population group: Arab Geographic origin: Jordan Method: Genomic DNA was isolated from peripheral blood samples of the patients and participating family members using QIAprep Spin Miniprep Kit. ES was performed on the proband patients of each family (Figure 1) by Partners HealthCare Personalized Medicine (PPM), Harvard, USA. Briefly, extracted DNA was sheared to 150â€“200 bp fragments. Exome enrichment was performed using Agilent SureSelect Human All Exon V5 kit (Santa Clara, Californian, U.S.A.). DNA was sequenced using 100 bp paired-end reads on Hiseq 2500 platform (Illumina Inc., San Diego, CA). Raw data were processed by Illumina base-calling software 1.7 using default parameters. The sequencing reads were aligned to the NCBI reference sequence (GRCh37), using the Burrows-Wheeler Aligner (BWA), and variant calls were made using the Genomic Analysis Tool Kit (GATK). The detected variants were annotated and filtered against four databases (i.e., NCBI CCDS (http://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi), RefSeq (http://www.ncbi.nlm.nih.-gov/) RefSeq/), Ensembl (http://www.ensembl.org), and Encode (http://genome.ucsc.edu/ENCODE)). Testing laboratory: Cell Therapy Center, Amman, Jordan Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Sex: male
Pathogenic (Aug 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ABCA4-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004113435.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The ABCA4 c.1648G>A variant is predicted to result in the amino acid substitution p.Gly550Arg. This variant has been reported many times as causative for autosomal … (more) The ABCA4 c.1648G>A variant is predicted to result in the amino acid substitution p.Gly550Arg. This variant has been reported many times as causative for autosomal recessive retinal dystrophy (see for examples Shroyer et al. 2001. PubMed ID: 11726554; Bertelsen et al. 2014. PubMed ID: 24713488; Table S1 in Stone. 2017. PubMed ID: 28559085; Zhu et al. 2021. PubMed ID: 33732702). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94528780-C-T). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99070/). Given the evidence, we interpret c.1648G>A (p.Gly550Arg) as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: research	Stargardt disease 3 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana Accession: SCV005046934.1 First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 35194496
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Retina International Accession: SCV000117550.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_ABCR:c.1648G>A
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Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24713488, 17982420, 22229821, 28559085, 30093795, 31589614, 33732702, 22264887, 24317291, 32619608, 31968401, 11726554, 11527935, 15192030, 33090715, 29925512)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 550 of the ABCA4 protein (p.Gly550Arg). This variant is present in population databases (rs61748558, gnomAD 0.003%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 11726554, 28559085, 29925512). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99070). 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%. For these reasons, this variant has been classified as Pathogenic.

Comment:

The ABCA4 c.1648G>A (p.Gly550Arg) missense variant has been identified in at least seven studies in which it is found in a total of seven individuals including in three in a compound heterozygous state with a known pathogenic variant and four in a heterozygous state with an undetected second allele (Shroyer et al., 2001; Briggs et al., 2001; Stenirri et al., 2004; Thiadens et al 2012; Bertelsen et al. 2014; Fujinami et al., 2015; Salles et al. 2018). Six of these individuals exhibited Stargardt disease and the seventh exhibited generalized choriocapillaris dystrophy. The p.Gly550Arg variant was absent from 100 control chromosomes (Shroyer et al., 2001) and is reported at a frequency of 0.00006 in the South Asian population of the Exome Aggregation Consortium, but this is based on one allele, so the variant is presumed to be rare. Based on the evidence, the p.Gly550Arg variant is classified as likely pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

The ABCA4 c.1648G>A variant is predicted to result in the amino acid substitution p.Gly550Arg. This variant has been reported many times as causative for autosomal recessive retinal dystrophy (see for examples Shroyer et al. 2001. PubMed ID: 11726554; Bertelsen et al. 2014. PubMed ID: 24713488; Table S1 in Stone. 2017. PubMed ID: 28559085; Zhu et al. 2021. PubMed ID: 33732702). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94528780-C-T). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99070/). Given the evidence, we interpret c.1648G>A (p.Gly550Arg) as pathogenic.

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
Mutation Screening of Six Exons of ABCA4 in Iranian Stargardt Disease Patients.	Darbari E	Journal of ophthalmic & vision research	2022	PMID: 35194496
Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.	Fujinami K	The British journal of ophthalmology	2019	PMID: 29925512
Variants in the ABCA4 gene in a Brazilian population with Stargardt disease.	Salles MV	Molecular vision	2018	PMID: 30093795
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
Clinical and molecular characteristics of childhood-onset Stargardt disease.	Fujinami K	Ophthalmology	2015	PMID: 25312043
Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies.	Bertelsen M	Investigative ophthalmology & visual science	2014	PMID: 24713488
Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy.	Thiadens AA	Ophthalmology	2012	PMID: 22264887
Denaturing HPLC profiling of the ABCA4 gene for reliable detection of allelic variations.	Stenirri S	Clinical chemistry	2004	PMID: 15192030
Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration.	Shroyer NF	Human molecular genetics	2001	PMID: 11726554
Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration.	Briggs CE	Investigative ophthalmology & visual science	2001	PMID: 11527935

Text-mined citations for rs61748558 ...

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.1648G>A (p.Gly550Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61748558 ...