Submissions for variant NM_000784.4(CYP27A1):c.1477-2A>C

dbSNP: rs111570247

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000432466	SCV000516582	likely pathogenic	not provided	2019-05-31	criteria provided, single submitter	clinical testing	Identified in two siblings with cerebrotendinous xanthomatosis in the presence of a second CYP27A1 variant (Chen et al., 2017); Canonical splice site variant predicted to result in the loss of a critical region.; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28623566)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001833525	SCV003524994	pathogenic	Cholestanol storage disease	2022-09-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 379475). Disruption of this splice site has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 28623566, 33414089). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs111570247, gnomAD 0.006%). This sequence change affects an acceptor splice site in intron 8 of the CYP27A1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Ambry Genetics	RCV004022314	SCV004077984	pathogenic	Cardiovascular phenotype	2023-07-05	criteria provided, single submitter	clinical testing	The c.1477-2A>C intronic variant results from an A to C substitution two nucleotides before exon 9 (coding exon 9) of the CYP27A1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported as a compound heterozygous finding in several individuals who were diagnosed with cerebrotendinous xanthomatosis either in infancy or as an adult (Chen, 2017; Zhang, 2021). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV001833525	SCV004190832	pathogenic	Cholestanol storage disease	2023-02-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001833525	SCV002078811	likely pathogenic	Cholestanol storage disease	2020-09-01	no assertion criteria provided	clinical testing