ClinVar Genomic variation as it relates to human health
NM_006371.5(CRTAP):c.634C>T (p.Arg212Ter)
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.
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(2); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006371.5(CRTAP):c.634C>T (p.Arg212Ter)
Variation ID: 344809 Accession: VCV000344809.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.3 3: 33124420 (GRCh38) [ NCBI UCSC ] 3: 33165912 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 6, 2016 Feb 28, 2024 Jan 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006371.5:c.634C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006362.1:p.Arg212Ter nonsense NM_001393363.1:c.634C>T NP_001380292.1:p.Arg212Ter nonsense NM_001393364.1:c.634C>T NP_001380293.1:p.Arg212Ter nonsense NM_001393365.1:c.484C>T NP_001380294.1:p.Arg162Ter nonsense NC_000003.12:g.33124420C>T NC_000003.11:g.33165912C>T NG_008122.1:g.15463C>T LRG_4:g.15463C>T LRG_4t1:c.634C>T LRG_4p1:p.Arg212Ter - Protein change
- R212*, R162*
- Other names
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- Canonical SPDI
- NC_000003.12:33124419:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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CRTAP | - | - |
GRCh38 GRCh37 |
576 | 655 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 6, 2024 | RCV000368253.15 |
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
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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
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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
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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. |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Osteogenesis imperfecta type 7
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000443222.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The CRTAP c.634C>T (p.Arg212Ter) variant is a stop-gained variant and has been reported in one study where it is found in a compound heterozygous state … (more)
The CRTAP c.634C>T (p.Arg212Ter) variant is a stop-gained variant and has been reported in one study where it is found in a compound heterozygous state with another stop-gained variant in one individual with osteogenesis imperfecta (Chang et al. 2010). Control data were unavailable for this variant, which is reported at a frequency of 0.00002 in the Total population of the Exome Aggregation Consortium. Western blotting experiments in individual fibroblasts showed that the CRTAP variant protein was absent (Chang et al. 2010). Due to the potential impact of stop-gained variants and the supporting evidence, the p.Arg212Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for osteogenesis imperfecta. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: research
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Osteogenesis imperfecta type 7
Affected status: yes
Allele origin:
germline
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Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS
Accession: SCV000920383.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019
Comment:
Nonsense variant
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Family history: no
Age: 0-9 years
Sex: male
Geographic origin: India
Tissue: fetus sample after autopsy
Method: whole exome sequencing; PCR; Sanger sequencing
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Pathogenic
(Jan 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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Osteogenesis imperfecta type 7
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001393981.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg212*) in the CRTAP gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg212*) in the CRTAP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRTAP are known to be pathogenic (PMID: 17055431, 19862557, 24715559). This variant is present in population databases (rs137853944, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with CRTAP-related osteogenesis imperfecta (PMID: 19846465, 31742715). ClinVar contains an entry for this variant (Variation ID: 344809). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Osteogenesis imperfecta type 7
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768922.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with osteogenesis imperfecta, type VII (MIM#610682). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (8 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Variants predicted or proven to result in NMD have been reported in multiple individuals in the context of osteogenesis imperfecta, type VII (ClinVar, PMID:17192541, 19846465, 21955071). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in a homozygous or compound heterozygous state in multiple individuals with osteogenesis imperfecta, type VII (ClinVar, PMID:31742715, 19846465). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1207 - Parental origin of the variant is unresolved. Trio analysis shows that both of this individual's parents are carriers of this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Exome sequencing for perinatal phenotypes: The significance of deep phenotyping. | Aggarwal S | Prenatal diagnosis | 2020 | PMID: 31742715 |
Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. | Van Dijk FS | American journal of medical genetics. Part A | 2014 | PMID: 24715559 |
Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix. | Valli M | Clinical genetics | 2012 | PMID: 21955071 |
Null mutations in LEPRE1 and CRTAP cause severe recessive osteogenesis imperfecta. | Marini JC | Cell and tissue research | 2010 | PMID: 19862557 |
Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex. | Chang W | Human molecular genetics | 2010 | PMID: 19846465 |
Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. | Barnes AM | The New England journal of medicine | 2006 | PMID: 17192541 |
CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. | Morello R | Cell | 2006 | PMID: 17055431 |
Text-mined citations for rs137853944 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.