VCV000005739.23 - ClinVar

NM_201253.3(CRB1):c.3307G>A (p.Gly1103Arg)

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.

(17)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_201253.3(CRB1):c.3307G>A (p.Gly1103Arg)

Variation ID: 5739 Accession: VCV000005739.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q31.3 1: 197435170 (GRCh38) [ NCBI UCSC ] 1: 197404300 (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	Sep 16, 2024	Apr 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_201253.3:c.3307G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_957705.1:p.Gly1103Arg	missense
NM_001193640.2:c.2971G>A	NP_001180569.1:p.Gly991Arg	missense
NM_001257965.2:c.3235G>A	NP_001244894.1:p.Gly1079Arg	missense
NM_001257966.2:c.2129-430G>A		intron variant
NR_047563.2:n.3260G>A		non-coding transcript variant
NR_047564.2:n.3468G>A		non-coding transcript variant
NC_000001.11:g.197435170G>A
NC_000001.10:g.197404300G>A
NG_008483.2:g.238709G>A
	P82279:p.Gly1103Arg

... more HGVS ... less HGVS

Protein change

G1103R, G1079R, G991R

Other names

Canonical SPDI

NC_000001.11:197435169:G:A

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) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

ClinGen: CA117711 UniProtKB: P82279#VAR_022974 OMIM: 604210.0011 dbSNP: rs62636275 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.
CRB1		-	-	GRCh38 GRCh37	1944	1969

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.
Leber congenital amaurosis 8	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 15, 2024	RCV000006093.10
Retinitis pigmentosa 12	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 14, 2024	RCV000006094.8
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 9, 2024	RCV000086341.7
Leber congenital amaurosis 8 Retinitis pigmentosa 12	Pathogenic (2)	criteria provided, single submitter	Jan 2, 2024	RCV000648818.10
Early-onset retinal dystrophy	Pathogenic (1)	no assertion criteria provided	Dec 13, 2017	RCV000786009.1
Leber congenital amaurosis	Pathogenic (2)	no assertion criteria provided	Sep 16, 2020	RCV001002998.2
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jan 22, 2019	RCV001073404.2
Pigmented paravenous retinochoroidal atrophy	Pathogenic (1)	criteria provided, single submitter	Apr 11, 2023	RCV003450617.1

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.
Pathogenic (Jan 22, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001238945.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa 12 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004801139.2 First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024
Pathogenic (Apr 09, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321519.6 First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024	Comment: 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: 16543197, … (more) 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: 16543197, 20956273, 22065545, 23449718, 26147992, 25133751, 17964524, 17724218, 19140180, 15024725, 31054281, 31456290, 31589614, 33441055, 35119454, 34884448, 33921607) (less)
Pathogenic (Apr 01, 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: SCV000339784.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (8) PubMed: 15024725‚ 16543197‚ 17724218‚ 17964524‚ 22065545‚ 23449718‚ 25133751‚ 26147992 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CRB1 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 12 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004180146.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 8 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004180144.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pigmented paravenous retinochoroidal atrophy Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004180145.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Jan 02, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Leber congenital amaurosis 8 Retinitis pigmentosa 12 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000770639.7 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 16543197‚ 19140180‚ 23449718 Comment: This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1103 of the CRB1 protein (p.Gly1103Arg). … (more) This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1103 of the CRB1 protein (p.Gly1103Arg). This variant is present in population databases (rs62636275, gnomAD 0.005%). This missense change has been observed in individuals with Leber congenital amaurosis or retinitis pigmentosa (PMID: 16543197, 19140180, 23449718). It is commonly reported in individuals of Israeli and Palestinian ancestry (PMID: 23449718). ClinVar contains an entry for this variant (Variation ID: 5739). 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 CRB1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 15, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 8 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211137.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Feb 15, 2009)	no assertion criteria provided Method: literature only	LEBER CONGENITAL AMAUROSIS 8 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026275.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 10, 2015	Publications: PubMed (3) PubMed: 16543197‚ 15024725‚ 19140180 Comment on evidence: In all 4 affected members of a family of Middle Eastern origin segregating autosomal recessive Leber congenital amaurosis-8 (LCA8; 613835) and high to extreme hyperopia, … (more) In all 4 affected members of a family of Middle Eastern origin segregating autosomal recessive Leber congenital amaurosis-8 (LCA8; 613835) and high to extreme hyperopia, Abouzeid et al. (2006) identified homozygosity for a 3307G-A transition in exon 9 of the CRB1 gene, resulting in a gly1103-to-arg (G1103R) substitution at a highly conserved site in the protein. The mutation was found in heterozygous state in 4 unaffected family members and was not found in 104 healthy Caucasian volunteers. Abouzeid et al. (2006) showed that hyperopia and LCA were linked to the mutant CRB1 gene itself and were not dependent on unlinked modifiers. Abouzeid et al. (2006) noted that the G1103R mutation had previously been identified in compound heterozygous state in a patient with sporadic LCA by Hanein et al. (2004). In affected members of a consanguineous family with early-onset retinitis pigmentosa (RP12; 600105), Benayoun et al. (2009) identified compound heterozygosity for the G1103R mutation and a 10-bp deletion (604210.0012) in the CRB1 gene. (less)
Pathogenic (Feb 15, 2009)	no assertion criteria provided Method: literature only	RETINITIS PIGMENTOSA 12 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026276.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 10, 2015	Publications: PubMed (3) PubMed: 16543197‚ 15024725‚ 19140180 Comment on evidence: In all 4 affected members of a family of Middle Eastern origin segregating autosomal recessive Leber congenital amaurosis-8 (LCA8; 613835) and high to extreme hyperopia, … (more) In all 4 affected members of a family of Middle Eastern origin segregating autosomal recessive Leber congenital amaurosis-8 (LCA8; 613835) and high to extreme hyperopia, Abouzeid et al. (2006) identified homozygosity for a 3307G-A transition in exon 9 of the CRB1 gene, resulting in a gly1103-to-arg (G1103R) substitution at a highly conserved site in the protein. The mutation was found in heterozygous state in 4 unaffected family members and was not found in 104 healthy Caucasian volunteers. Abouzeid et al. (2006) showed that hyperopia and LCA were linked to the mutant CRB1 gene itself and were not dependent on unlinked modifiers. Abouzeid et al. (2006) noted that the G1103R mutation had previously been identified in compound heterozygous state in a patient with sporadic LCA by Hanein et al. (2004). In affected members of a consanguineous family with early-onset retinitis pigmentosa (RP12; 600105), Benayoun et al. (2009) identified compound heterozygosity for the G1103R mutation and a 10-bp deletion (604210.0012) in the CRB1 gene. (less)
Pathogenic (Dec 13, 2017)	no assertion criteria provided Method: research	Early-onset retinal dystrophy Affected status: yes Allele origin: inherited	Molecular Genetics Laboratory, Institute for Ophthalmic Research Accession: SCV000924649.1 First in ClinVar: Jun 28, 2019 Last updated: Jun 28, 2019
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	leber congenital amaurosis Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001161052.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020
Pathogenic (-)	no assertion criteria provided Method: research	Leber congenital amaurosis 8 Affected status: yes Allele origin: inherited	Laboratory of Genetics in Ophthalmology, Institut Imagine Accession: SCV001425486.1 First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020	Publications: PubMed (1) PubMed: 15024725 Number of individuals with the variant: 2
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Leber congenital amaurosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460950.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Retina International Accession: SCV000118487.1 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_CRB1:c.3307G>A
not provided (-)	no classification provided Method: phenotyping only	Leber congenital amaurosis 8 Retinitis pigmentosa 12 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline, unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749793.2 First in ClinVar: Jul 18, 2021 Last updated: Jun 17, 2024	Comment: Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 11-23-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are … (more) Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 11-23-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Abnormal retinal morphology (present) Age: 10-19 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-03-20 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Abnormal retinal morphology (present) Indication for testing: Diagnostic Age: 0-9 years Sex: male Testing laboratory: Invitae Date variant was reported to submitter: 2020-11-23 Testing laboratory interpretation: Pathogenic
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Comment:

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: 16543197, 20956273, 22065545, 23449718, 26147992, 25133751, 17964524, 17724218, 19140180, 15024725, 31054281, 31456290, 31589614, 33441055, 35119454, 34884448, 33921607)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1103 of the CRB1 protein (p.Gly1103Arg). This variant is present in population databases (rs62636275, gnomAD 0.005%). This missense change has been observed in individuals with Leber congenital amaurosis or retinitis pigmentosa (PMID: 16543197, 19140180, 23449718). It is commonly reported in individuals of Israeli and Palestinian ancestry (PMID: 23449718). ClinVar contains an entry for this variant (Variation ID: 5739). 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 CRB1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 11-23-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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
Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families.	Srilekha S	PloS one	2015	PMID: 26147992
Mutation screening of retinal dystrophy patients by targeted capture from tagged pooled DNAs and next generation sequencing.	Watson CM	PloS one	2014	PMID: 25133751
Mutations in CRB1 are a relatively common cause of autosomal recessive early-onset retinal degeneration in the Israeli and Palestinian populations.	Beryozkin A	Investigative ophthalmology & visual science	2013	PMID: 23449718
CRB1 mutations in inherited retinal dystrophies.	Bujakowska K	Human mutation	2012	PMID: 22065545
Genetic heterogeneity in two consanguineous families segregating early onset retinal degeneration: the pitfalls of homozygosity mapping.	Benayoun L	American journal of medical genetics. Part A	2009	PMID: 19140180
Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture.	Stone EM	American journal of ophthalmology	2007	PMID: 17964524
Clinical and molecular genetics of Leber's congenital amaurosis: a multicenter study of Italian patients.	Simonelli F	Investigative ophthalmology & visual science	2007	PMID: 17724218
A G1103R mutation in CRB1 is co-inherited with high hyperopia and Leber congenital amaurosis.	Abouzeid H	Ophthalmic genetics	2006	PMID: 16543197
Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis.	Hanein S	Human mutation	2004	PMID: 15024725
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CRB1	-	-	-	-

Text-mined citations for rs62636275 ...

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_201253.3(CRB1):c.3307G>A (p.Gly1103Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62636275 ...