VCV000636015.12 - ClinVar

NM_201253.3(CRB1):c.1892A>G (p.Tyr631Cys)

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.

(6)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_201253.3(CRB1):c.1892A>G (p.Tyr631Cys)

Variation ID: 636015 Accession: VCV000636015.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q31.3 1: 197421720 (GRCh38) [ NCBI UCSC ] 1: 197390850 (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	Jul 22, 2019	Jun 17, 2024	Mar 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_201253.3:c.1892A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_957705.1:p.Tyr631Cys	missense
NM_001193640.2:c.1556A>G	NP_001180569.1:p.Tyr519Cys	missense
NM_001257965.2:c.1685A>G	NP_001244894.1:p.Tyr562Cys	missense
NM_001257966.2:c.1892A>G	NP_001244895.1:p.Tyr631Cys	missense
NR_047564.2:n.2053A>G		non-coding transcript variant
NC_000001.11:g.197421720A>G
NC_000001.10:g.197390850A>G
NG_008483.2:g.225259A>G

... more HGVS ... less HGVS

Protein change

Y631C, Y519C, Y562C

Other names

Canonical SPDI

NC_000001.11:197421719: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

dbSNP: rs1271816211 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	1943	1968

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.
Retinitis pigmentosa	Uncertain significance (1)	no assertion criteria provided	Apr 1, 2018	RCV000787575.1
Leber congenital amaurosis 8 Retinitis pigmentosa 12	Pathogenic (1)	criteria provided, single submitter	Nov 1, 2023	RCV000795927.6
Leber congenital amaurosis 8	Likely pathogenic (2)	criteria provided, single submitter	Mar 28, 2024	RCV001250596.4
Leber congenital amaurosis	Likely pathogenic (1)	no assertion criteria provided	Oct 20, 2020	RCV001830677.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Nov 7, 2019	RCV001766622.3

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.
Uncertain significance (Nov 07, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001988963.2 First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30092450, 28341475, … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30092450, 28341475, 31047448, 27157150, 30718709, 30956116, 32831148) (less)
Pathogenic (Nov 01, 2023)	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: SCV000935408.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 27157150‚ 28341475‚ 30718709 Comment: This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 631 of the CRB1 protein … (more) This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 631 of the CRB1 protein (p.Tyr631Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with CRB1-related conditions (PMID: 27157150, 28341475, 30718709). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 636015). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CRB1 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Mar 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 8 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211097.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Apr 01, 2018)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926555.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Uncertain significance (-)	no assertion criteria provided Method: research	Leber congenital amaurosis 8 Affected status: yes Allele origin: maternal	Laboratory of Genetics in Ophthalmology, Institut Imagine Accession: SCV001425464.1 First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020	Number of individuals with the variant: 1
Likely pathogenic (Oct 20, 2020)	no assertion criteria provided Method: clinical testing	Leber congenital amaurosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002090151.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30092450, 28341475, 31047448, 27157150, 30718709, 30956116, 32831148)

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 631 of the CRB1 protein (p.Tyr631Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with CRB1-related conditions (PMID: 27157150, 28341475, 30718709). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 636015). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CRB1 protein function. For these reasons, this variant has been classified 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
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Genotypic and Phenotypic Characteristics of CRB1-Associated Retinal Dystrophies: A Long-Term Follow-up Study.	Talib M	Ophthalmology	2017	PMID: 28341475
Retinal Dystrophy in 6 Young Patients Who Presented with Intermediate Uveitis.	Hettinga YM	Ophthalmology	2016	PMID: 27157150

Text-mined citations for rs1271816211 ...

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.1892A>G (p.Tyr631Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1271816211 ...