NM_006371.5(CRTAP):c.3G>A (p.Met1Ile) AND Osteogenesis imperfecta

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 4, 2022
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:: RCV002468961.1

Allele description [Variation Report for NM_006371.5(CRTAP):c.3G>A (p.Met1Ile)]

NM_006371.5(CRTAP):c.3G>A (p.Met1Ile)

Genes:

LOC129936436:ATAC-STARR-seq lymphoblastoid silent region 14183 [Gene]
CRTAP:cartilage associated protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.3

Genomic location:

Preferred name:

NM_006371.5(CRTAP):c.3G>A (p.Met1Ile)

HGVS:

NC_000003.12:g.33114080G>A
NG_008122.1:g.5123G>A
NM_001393363.1:c.3G>A
NM_001393364.1:c.3G>A
NM_001393365.1:c.3G>A
NM_006371.5:c.3G>AMANE SELECT
NP_001380292.1:p.Met1Ile
NP_001380293.1:p.Met1Ile
NP_001380294.1:p.Met1Ile
NP_006362.1:p.Met1Ile
LRG_4t1:c.3G>A
LRG_4:g.5123G>A
NC_000003.11:g.33155572G>A
NM_006371.4:c.3G>A

Protein change:

M1I; MET1ILE

Links:

OMIM: 605497.0005; dbSNP: rs72659357

NCBI 1000 Genomes Browser:

rs72659357

Molecular consequence:

NM_001393363.1:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001393364.1:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001393365.1:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_006371.5:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001393363.1:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001393364.1:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001393365.1:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006371.5:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Osteogenesis imperfecta (OI)
Identifiers:: MONDO: MONDO:0019019; MeSH: D010013; MedGen: C0029434; OMIM: PS166200

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Foxd3 forkhead box D3 [Rattus norvegicus]
Foxd3 forkhead box D3 [Rattus norvegicus]
Gene ID:29203

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002766320	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 4, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002766320

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Nov 4, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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

Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta.

Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, Leikin S, Makareeva E, Kuznetsova N, Uveges TE, Ashok A, Flor AW, Mulvihill JJ, Wilson PL, Sundaram UT, Lee B, Marini JC.

N Engl J Med. 2006 Dec 28;355(26):2757-64.

PubMed [citation]

PMID:: 17192541
PMCID:: PMC7509984

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002766320.2

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

Description

Variant summary: CRTAP c.3G>A (p.Met1?, aka p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The first potential downstream in-frame start codon (ATG) is located in exon 1 at Met42. Several truncations have been reported 5' of Met42 in the CRTAP gene in affected individuals (HGMD). The variant was absent in 72958 control chromosomes (gnomAD). The variant, c.3G>A, has been reported in the literature in an infant affected with Osteogenesis Imperfecta, who carried a frameshift variant in trans (Barnes_2006). Authors of this study also analyzed patient derived cells, and reported that the father of the infant, whose variant alters the start codon, produced both normal and a smaller size CRTAP protein, suggesting that his cells contain a truncated form of CRTAP (likely initiated at the next methionine codon, Met42), and although they could not detect the truncated form in the infant, collagen prolyl 3-hydroxylation measurements suggested that the infant had some residual enzyme activity, supposedly derived from the paternal allele (Barnes_2006). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely 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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