Submissions for variant NM_006371.5(CRTAP):c.471+2C>A

gnomAD frequency: 0.00010  dbSNP: rs137853943

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190575	SCV000245594	pathogenic	Osteogenesis imperfecta type 7	2014-07-02	criteria provided, single submitter	clinical testing	The c.471+2C>A variant in CRTAP has been reported in 2 homozygous and 1 compound heterozygous individuals with Osteogenesis imperfecta type II (Bodian 2009, Van Dijk 2009) and was found to segregate with disease in 2 affected family members (Van Dijk 2009). Data from large population studies is insufficient to assess the frequency of this variant. This variant occurs in the +/- 1/2 region of the splice sequence and functional studies indicate this variant leads to aberrant splicing (Van Dijk 2009). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon the predicted impact to the protein, segregation studies, and functional evidence.
GeneDx	RCV000255275	SCV000322324	pathogenic	not provided	2021-02-27	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18996919, 19550437, 21239989, 31980526, 31589614)
Invitae	RCV000190575	SCV000763318	pathogenic	Osteogenesis imperfecta type 7	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 1 of the CRTAP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CRTAP are known to be pathogenic (PMID: 17055431, 19862557, 24715559). This variant is present in population databases (rs137853943, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with osteogenesis imperfecta (PMID: 18996919, 19550437). ClinVar contains an entry for this variant (Variation ID: 208570). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000190575	SCV000915046	likely pathogenic	Osteogenesis imperfecta type 7	2018-11-12	criteria provided, single submitter	clinical testing	The CRTAP c.471+2C>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.471+2C>A variant has been reported two studies and is found in a total of five individuals with osteogenesis imperfecta, including in two in a homozygous state, and in three in a compound heterozygous state from the same family (Bodian et al. 2009; Van Dijk et al. 2009). Control data are unavailable for this variant, which is reported at a frequency of 0.0002 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and due to the potential impact of splice donor variants, the c.471+2C>A variant is classified as likely pathogenic for osteogenesis imperfect. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000190575	SCV002047796	pathogenic	Osteogenesis imperfecta type 7	2021-02-17	criteria provided, single submitter	clinical testing	The CRTAP c.471+2C>A variant (rs137853943) has been published in the homozygous and compound heterozygous state in individuals with osteogenesis imperfecta (Bodian 2009, Van Dijk 2009). The variant is reported as pathogenic or likely pathogenic in the ClinVar database (Variation ID: 208570) and is listed in the general population with an overall allele frequency of 0.008% (18/213,550 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 1, which is likely to negatively impact gene function and one functional study supports this prediction (Van Dijk 2009). Based on available information, this variant is classified as pathogenic. References: Bodian DL et al. Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype-phenotype relationships. Hum Mol Genet. 2009 Feb 1;18(3):463-71. Van Dijk FS et al. CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis. Eur J Hum Genet. 2009 Dec;17(12):1560-9.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277445	SCV002564818	pathogenic	Osteogenesis imperfecta	2019-12-01	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000190575	SCV003807924	pathogenic	Osteogenesis imperfecta type 7	2022-04-08	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 moderated, PP1 supporting
PreventionGenetics, part of Exact Sciences	RCV003927754	SCV004740682	pathogenic	CRTAP-related condition	2023-12-20	criteria provided, single submitter	clinical testing	The CRTAP c.471+2C>A variant is predicted to interfere with splicing. This variant was reported in the homozygous state in a patient with osteogenesis imperfecta, who was born to non-consanguineous parents (Bodian et al. 2009. PubMed ID: 18996919). This variant was also reported in the compound heterozygous state in another patient with osteogenesis imperfecta, and RNA study suggested this variant affected splicing (Van Dijk et al. 2009. PubMed ID: 19550437)This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.