ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.1184+1G>A (rs587778777)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255284 SCV000322121 pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing The c.1184+1G>A pathogenic variant in the CYP27A1 gene has been reported previously in the both the homozygous and compound heterozygous states in individuals with cerebrotendinous xanthomatosis (Garuti et al., 1997; Verrips et al, 2000; Lee et al., 2001;). Functional studies of this variant demonstrated it leads to the production of three abnormal transcripts, and almost undetectable levels of mRNA in patient fibroblasts (Garuti et al., 1997). This splice site variant destroys the canonical splice donor site in intron 6. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1184+1G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1184+1G>A as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255284 SCV000857447 pathogenic not provided 2017-10-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000056073 SCV000893579 pathogenic Cholestanol storage disease 2018-10-31 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000056073 SCV001193887 pathogenic Cholestanol storage disease 2019-12-24 criteria provided, single submitter clinical testing NM_000784.3(CYP27A1):c.1184+1G>A is classified as pathogenic in the context of cerebrotendinous xanthomatosis. Sources cited for classification include the following: PMID 22878431, 27084087, 11181744 and 9392430. Classification of NM_000784.3(CYP27A1):c.1184+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000056073 SCV001205319 pathogenic Cholestanol storage disease 2020-10-25 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 6 of the CYP27A1 gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587778777, ExAC 0.07%). This variant has been observed in several individuals affected with cerebrotendinous xanthomatosis (PMID: 9392430, 28894950, 21645175). This variant is also known as In6+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 65833). Studies have shown that this variant is associated with the skipping of 89 nucleotides of exon 6, which introduces a frameshift (PMID:9392430). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company RCV000056073 SCV001424398 pathogenic Cholestanol storage disease criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000255284 SCV001446960 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
GeneReviews RCV000056073 SCV000087138 pathologic Cholestanol storage disease 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000056073 SCV001455787 pathogenic Cholestanol storage disease 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000255284 SCV001742873 pathogenic not provided no assertion criteria provided clinical testing

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