Submissions for variant NM_000784.4(CYP27A1):c.562C>T (p.Arg188Ter)

gnomAD frequency: 0.00004  dbSNP: rs188850202

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000987032	SCV001136214	pathogenic	Cholestanol storage disease	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000987032	SCV001207851	pathogenic	Cholestanol storage disease	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg188*) in the CYP27A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP27A1 are known to be pathogenic (PMID: 9392430, 10775536, 26937392). This variant is present in population databases (rs188850202, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 28623566). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 801897). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000987032	SCV004192660	pathogenic	Cholestanol storage disease	2024-01-16	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000987032	SCV005382397	pathogenic	Cholestanol storage disease	2023-05-20	criteria provided, single submitter	clinical testing	The observed stop gained c.562C>T(p.Arg188Ter) variant in CYP27A1 gene has been reported in compound heterozygous state in individual(s) affected with cerebrotendinous xanthomatosis (Chen C, et. al., 2017). This variant is present with an allele frequency of 0.006% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The nucleotide change c.562C>T in CYP27A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in CYP27A1 are known to be pathogenic (Verrips A, et. al., 2000). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in CYP27A1 gene, the molecular diagnosis is not confirmed
Fulgent Genetics, Fulgent Genetics	RCV000987032	SCV005647739	pathogenic	Cholestanol storage disease	2024-03-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000987032	SCV002078774	pathogenic	Cholestanol storage disease	2020-10-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003928633	SCV004742287	pathogenic	CYP27A1-related disorder	2023-10-24	no assertion criteria provided	clinical testing	The CYP27A1 c.562C>T variant is predicted to result in premature protein termination (p.Arg188*). This variant has been reported in the compound heterozygous state in an individual presenting with Cerebrotendinous xanthomatosis (CTX) (Family 4, Table 1, Chen et al. 2017. PubMed ID: 28623566). This variant is reported in 0.035% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219677060-C-T). Nonsense variants in CYP27A1 are expected to be pathogenic. This variant is interpreted as pathogenic.