VCV000099217.16 - ClinVar

NM_000350.3(ABCA4):c.32T>C (p.Leu11Pro)

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.

(10)

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.32T>C (p.Leu11Pro)

Variation ID: 99217 Accession: VCV000099217.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94121014 (GRCh38) [ NCBI UCSC ] 1: 94586570 (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	Feb 14, 2024	Jan 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.32T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Leu11Pro	missense
NM_001425324.1:c.32T>C	NP_001412253.1:p.Leu11Pro	missense
NC_000001.11:g.94121014A>G
NC_000001.10:g.94586570A>G
NG_009073.1:g.5136T>C
NG_009073.2:g.5134T>C
	P78363:p.Leu11Pro

... more HGVS ... less HGVS

Protein change

L11P

Other names

NP_000341.2:p.(Leu11Pro)

Canonical SPDI

NC_000001.11:94121013:A:G

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA227106 UniProtKB: P78363#VAR_012493 dbSNP: rs62645946 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/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 22, 2024	RCV000085568.8
ABCA4-related disorder	Pathogenic (1)	criteria provided, single submitter	Dec 4, 2018	RCV000779010.5
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jan 23, 2019	RCV001074134.3
Retinitis pigmentosa	Likely pathogenic (1)	criteria provided, single submitter	Apr 1, 2021	RCV001723665.4
Severe early-childhood-onset retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Mar 22, 2022	RCV002051808.2
Age related macular degeneration 2	Pathogenic (1)	criteria provided, single submitter	May 4, 2022	RCV002247489.2
Cone-rod dystrophy	Pathogenic (1)	criteria provided, single submitter	Jul 24, 2023	RCV003324509.3
Stargardt disease	Pathogenic (1)	criteria provided, single submitter	Jul 24, 2023	RCV003324510.3

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 (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Age related macular degeneration 2 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002517492.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Dec 04, 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: SCV000915451.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (5) PubMed: 23755871‚ 30093795‚ 9781034‚ 19365591‚ 17325136 Comment: The ABCA4 c.32T>C (p.Leu11Pro) missense variant has been reported in at least six studies in which it is found in a total of eight individuals, … (more) The ABCA4 c.32T>C (p.Leu11Pro) missense variant has been reported in at least six studies in which it is found in a total of eight individuals, including in a compound heterozygous state in six subjects diagnosed with Stargardt disease (STGD), and in a heterozygous state in one individual with STGD and one with late onset fundus flavimaculatus (Rozet et al. 1998; Valverde et al. 2007; Maia-Lopes et al. 2009; Riveiro-Alvarez et al. 2013; Salles et al. 2018). The p.Leu11Pro variant was absent from 110 healthy controls and is reported at a frequency of 0.000015 in the European (non-Finnish) 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.Leu11Pro variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Jan 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: SCV001239703.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Likely pathogenic (Apr 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Retinitis pigmentosa (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001950201.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (6) PubMed: 34906470‚ 9781034‚ 17325136‚ 19365591‚ 23755871‚ 30093795 Comment: The p.Leu11Pro variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more) The p.Leu11Pro variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3-S. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
Pathogenic (Jan 22, 2024)	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: SCV001587237.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 17325136‚ 19365591‚ 29925512‚ 30093795 Comment: This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 11 of the ABCA4 protein (p.Leu11Pro). … (more) This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 11 of the ABCA4 protein (p.Leu11Pro). This variant is present in population databases (rs62645946, gnomAD 0.0009%). This missense change has been observed in individual(s) with ABCA4-related conditions (PMID: 17325136, 19365591, 29925512, 30093795). 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: 99217). 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)
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe early-childhood-onset retinal dystrophy Affected status: yes Allele origin: germline	3billion Accession: SCV002318729.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (3) PubMed: 19365591‚ 9781034‚ 17325136 Comment: Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099217, PMID:9781034). … (more) Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099217, PMID:9781034). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 19365591). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 17325136). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.948>=0.6, 3CNET: 0.972>=0.75). A missense variant is a common mechanism associated with Stargardt disease 1. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Large central visual field defect (present) , Macular dystrophy (present)
Likely pathogenic (Jun 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501243.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (5) PubMed: 9781034‚ 19074458‚ 32619608‚ 29925512‚ 30093795 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Stargardt disease Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030387.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PM2, PP2, PM2, PP3, PP5.	Publications: PubMed (2) PubMed: 36909829‚ 35903041 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 1 Geographic origin: Portugal
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cone-rod dystrophy Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030398.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PM2, PP2, PM2, PP3, PP5.	Publications: PubMed (2) PubMed: 36909829‚ 35903041 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 1 Geographic origin: Portugal
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Retina International Accession: SCV000117705.1 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.32T>C

Comment:

The ABCA4 c.32T>C (p.Leu11Pro) missense variant has been reported in at least six studies in which it is found in a total of eight individuals, including in a compound heterozygous state in six subjects diagnosed with Stargardt disease (STGD), and in a heterozygous state in one individual with STGD and one with late onset fundus flavimaculatus (Rozet et al. 1998; Valverde et al. 2007; Maia-Lopes et al. 2009; Riveiro-Alvarez et al. 2013; Salles et al. 2018). The p.Leu11Pro variant was absent from 110 healthy controls and is reported at a frequency of 0.000015 in the European (non-Finnish) 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.Leu11Pro variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

The p.Leu11Pro variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3-S. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 11 of the ABCA4 protein (p.Leu11Pro). This variant is present in population databases (rs62645946, gnomAD 0.0009%). This missense change has been observed in individual(s) with ABCA4-related conditions (PMID: 17325136, 19365591, 29925512, 30093795). 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: 99217). 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:

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099217, PMID:9781034). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 19365591). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 17325136). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.948>=0.6, 3CNET: 0.972>=0.75). A missense variant is a common mechanism associated with Stargardt disease 1. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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
The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.	Peter VG	PNAS nexus	2023	PMID: 36909829
Anisometropia and asymmetric ABCA4-related cone-rod dystrophy.	Santos C	Ophthalmic genetics	2022	PMID: 35903041
The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK).	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34906470
Genotype-Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants.	Del Pozo-Valero M	American journal of ophthalmology	2020	PMID: 32619608
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
Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families.	Riveiro-Alvarez R	Ophthalmology	2013	PMID: 23755871
ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis.	Maia-Lopes S	Molecular vision	2009	PMID: 19365591
ABCA4 disease progression and a proposed strategy for gene therapy.	Cideciyan AV	Human molecular genetics	2009	PMID: 19074458
Spectrum of the ABCA4 gene mutations implicated in severe retinopathies in Spanish patients.	Valverde D	Investigative ophthalmology & visual science	2007	PMID: 17325136
Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies.	Rozet JM	European journal of human genetics : EJHG	1998	PMID: 9781034
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Text-mined citations for rs62645946 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000350.3(ABCA4):c.32T>C (p.Leu11Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62645946 ...