Submissions for variant NM_000784.4(CYP27A1):c.1591del (p.Cys531fs)

gnomAD frequency: 0.00001  dbSNP: rs755723759

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669096	SCV000793801	uncertain significance	Cholestanol storage disease	2017-08-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000669096	SCV003467748	uncertain significance	Cholestanol storage disease	2022-07-14	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the CYP27A1 gene (p.Cys531Alafs*59). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1 amino acid(s) of the CYP27A1 protein and extend the protein by 57 additional amino acid residues. This variant is present in population databases (rs755723759, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. 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: 553613). 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.
Ambry Genetics	RCV004026106	SCV003963129	uncertain significance	Cardiovascular phenotype	2023-03-21	criteria provided, single submitter	clinical testing	Not expected to trigger nonsense-mediated mRNA decay Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782503	SCV005395064	uncertain significance	not specified	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: CYP27A1 c.1591delT (p.Cys531AlafsX59) located in the last exon (exon 9) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 2.8e-05 in 251450 control chromosomes in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1591delT has been reported in the literature in individuals within a cohort of newborns small for gestational age (example, Zhang_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Cerebrotendinous Xanthomatosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 37147621). ClinVar contains an entry for this variant (Variation ID: 553613). Based on the evidence outlined above, the variant was classified as uncertain significance.