NM_201253.3(CRB1):c.2548G>A (p.Gly850Ser) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 6, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000684930.5

Allele description [Variation Report for NM_201253.3(CRB1):c.2548G>A (p.Gly850Ser)]

NM_201253.3(CRB1):c.2548G>A (p.Gly850Ser)

Gene:

CRB1:crumbs cell polarity complex component 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q31.3

Genomic location:

Preferred name:

NM_201253.3(CRB1):c.2548G>A (p.Gly850Ser)

HGVS:

NC_000001.11:g.197427873G>A
NG_008483.2:g.231412G>A
NM_001193640.2:c.2212G>A
NM_001257965.2:c.2341G>A
NM_001257966.2:c.2128+5917G>A
NM_201253.3:c.2548G>AMANE SELECT
NP_001180569.1:p.Gly738Ser
NP_001244894.1:p.Gly781Ser
NP_957705.1:p.Gly850Ser
NC_000001.10:g.197397003G>A
NM_201253.2:c.2548G>A
NR_047563.2:n.2501G>A
NR_047564.2:n.2709G>A

Protein change:

G738S

Links:

dbSNP: rs776591659

NCBI 1000 Genomes Browser:

rs776591659

Molecular consequence:

NM_001257966.2:c.2128+5917G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001193640.2:c.2212G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001257965.2:c.2341G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201253.3:c.2548G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_047563.2:n.2501G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_047564.2:n.2709G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Retinitis pigmentosa 12 (RP12)
Synonyms:: RP 12; RP WITH OR WITHOUT PPRPE; RP WITH OR WITHOUT PRESERVED PARAARTERIOLE RETINAL PIGMENT EPITHELIUM; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010818; MedGen: C1838647; Orphanet: 791; OMIM: 600105

Name:: Leber congenital amaurosis 8 (LCA8)
Identifiers:: MONDO: MONDO:0013453; MedGen: C3151202; Orphanet: 65; OMIM: 613835

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000812393	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 6, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15459956, 20591486, 20956273, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000812393

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 6, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CRB1 mutation spectrum in inherited retinal dystrophies.

den Hollander AI, Davis J, van der Velde-Visser SD, Zonneveld MN, Pierrottet CO, Koenekoop RK, Kellner U, van den Born LI, Heckenlively JR, Hoyng CB, Handford PA, Roepman R, Cremers FP.

Hum Mutat. 2004 Nov;24(5):355-69. Review.

PubMed [citation]

PMID:: 15459956

Development of a diagnostic genetic test for simplex and autosomal recessive retinitis pigmentosa.

Clark GR, Crowe P, Muszynska D, O'Prey D, O'Neill J, Alexander S, Willoughby CE, McKay GJ, Silvestri G, Simpson DA.

Ophthalmology. 2010 Nov;117(11):2169-77.e3. doi: 10.1016/j.ophtha.2010.02.029. Epub 2010 Jun 29.

PubMed [citation]

PMID:: 20591486

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000812393.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 850 of the CRB1 protein (p.Gly850Ser). This variant is present in population databases (rs776591659, gnomAD 0.004%). This missense change has been observed in individuals with CRB1-related diseases and Leber congenital amaurosis (PMID: 15459956, 20591486, 20956273). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 565382). 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 95%. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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