NM_201253.3(CRB1):c.2234C>T (p.Thr745Met) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 2, 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:: RCV000809110.8

Allele description [Variation Report for NM_201253.3(CRB1):c.2234C>T (p.Thr745Met)]

NM_201253.3(CRB1):c.2234C>T (p.Thr745Met)

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.2234C>T (p.Thr745Met)

HGVS:

NC_000001.11:g.197427559C>T
NG_008483.2:g.231098C>T
NM_001193640.2:c.1898C>T
NM_001257965.2:c.2027C>T
NM_001257966.2:c.2128+5603C>T
NM_201253.3:c.2234C>TMANE SELECT
NP_001180569.1:p.Thr633Met
NP_001244894.1:p.Thr676Met
NP_957705.1:p.Thr745Met
NC_000001.10:g.197396689C>T
NM_201253.2:c.2234C>T
NR_047563.2:n.2187C>T
NR_047564.2:n.2395C>T
P82279:p.Thr745Met
p.(Thr745Met)

Protein change:

T633M; THR745MET

Links:

UniProtKB: P82279#VAR_011643; OMIM: 604210.0005; dbSNP: rs28939720

NCBI 1000 Genomes Browser:

rs28939720

Molecular consequence:

NM_001257966.2:c.2128+5603C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001193640.2:c.1898C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001257965.2:c.2027C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_201253.3:c.2234C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_047563.2:n.2187C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_047564.2:n.2395C>T - 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
SCV000949250	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10508521, 15024725, 20956273, 22968130, 23449718, 24715753, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000949250

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 2, 2024)

germline

clinical testing

PubMed (7)
[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

Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12).

den Hollander AI, ten Brink JB, de Kok YJ, van Soest S, van den Born LI, van Driel MA, van de Pol DJ, Payne AM, Bhattacharya SS, Kellner U, Hoyng CB, Westerveld A, Brunner HG, Bleeker-Wagemakers EM, Deutman AF, Heckenlively JR, Cremers FP, Bergen AA.

Nat Genet. 1999 Oct;23(2):217-21.

PubMed [citation]

PMID:: 10508521

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, Perrault I, Gerber S, Tanguy G, Barbet F, Ducroq D, Calvas P, Dollfus H, Hamel C, Lopponen T, Munier F, Santos L, Shalev S, Zafeiriou D, Dufier JL, Munnich A, Rozet JM, Kaplan J.

Hum Mutat. 2004 Apr;23(4):306-17.

PubMed [citation]

PMID:: 15024725

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000949250.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 745 of the CRB1 protein (p.Thr745Met). This variant is present in population databases (rs28939720, gnomAD 0.01%). This missense change has been observed in individual(s) with retinitis pigmentosa and/or Leber congenital amaurosis (PMID: 10508521, 15024725, 20956273, 23449718, 24715753). 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: 5733). 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%. This variant disrupts the p.Thr745 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been observed in individuals with CRB1-related conditions (PMID: 10508521, 15024725, 20956273, 22968130, 23449718, 24715753), which suggests that this may be a clinically significant amino acid residue. 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: Apr 15, 2024

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