Submissions for variant NM_000784.4(CYP27A1):c.1017G>A (p.Thr339=)

gnomAD frequency: 0.00010  dbSNP: rs200553205

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000397921	SCV000336832	uncertain significance	not provided	2018-01-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000665225	SCV000789306	uncertain significance	Cholestanol storage disease	2017-01-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000665225	SCV000896932	uncertain significance	Cholestanol storage disease	2018-10-31	criteria provided, single submitter	clinical testing
Clinical Genetics, Amsterdam Medical Centre	RCV000665225	SCV001468517	likely benign	Cholestanol storage disease	2021-01-08	criteria provided, single submitter	clinical testing	Variant homozygously found in a 74 years old women without characteristic phenotype. RNA analysis revealed no effect on splicing.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665225	SCV001557128	uncertain significance	Cholestanol storage disease	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change affects codon 339 of the CYP27A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CYP27A1 protein. This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs200553205, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CYP27A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 284271). 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 create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282102	SCV002571958	uncertain significance	not specified	2022-08-11	criteria provided, single submitter	clinical testing	Variant summary: CYP27A1 c.1017G>A (p.Thr339Thr) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens the same 5' donor site. One submitter in ClinVar (SCV001468517.1) reports that the variant was found in the homozygous state in a 74 year old woman, where RNA analysis revealed no impact on splicing. However, this is yet to be confirmed by published functional studies. The variant allele was found at a frequency of 9.3e-05 in 247182 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CYP27A1 causing Cerebrotendinous Xanthomatosis (9.3e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1017G>A in individuals affected with Cerebrotendinous Xanthomatosis and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000665225	SCV002078791	uncertain significance	Cholestanol storage disease	2020-02-26	no assertion criteria provided	clinical testing