Submissions for variant NM_000784.4(CYP27A1):c.256-1G>T

dbSNP: rs886556800

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668882	SCV000793556	likely pathogenic	Cholestanol storage disease	2017-08-18	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000728856	SCV000856474	pathogenic	not provided	2017-08-29	criteria provided, single submitter	clinical testing
Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile	RCV000668882	SCV000897999	pathogenic	Cholestanol storage disease	2014-04-07	criteria provided, single submitter	research	This patient is a compound heterozygote for the substitution c.256-1G>T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the pathogenic mutation c.1183C>T(p.Arg395Cys).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668882	SCV002240818	pathogenic	Cholestanol storage disease	2024-03-27	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 1 of the CYP27A1 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 CYP27A1 are known to be pathogenic (PMID: 9392430, 10775536, 26937392). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 25983621). ClinVar contains an entry for this variant (Variation ID: 553433). 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.
Baylor Genetics	RCV000668882	SCV004190834	pathogenic	Cholestanol storage disease	2023-01-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748891	SCV005356437	pathogenic	CYP27A1-related disorder	2024-05-16	no assertion criteria provided	clinical testing	The CYP27A1 c.256-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported along with a known pathogenic CYP27A1 missense variant (c.1183C>T, p.Arg395Cys) in an individual with cerebrotendinous xanthomatosis (Smalley et al. 2015. PubMed ID: 25983621). RNA studies have shown that the c.256-1G>T variant results in skipping of exon 2 (Smalley et al. 2015. PubMed ID: 25983621). This variant has not been reported in a large population database, indicating it is rare. Variants that disrupt the consensus splice acceptor site in CYP27A1 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.