Submissions for variant NM_000784.4(CYP27A1):c.958C>T (p.Leu320Phe)

gnomAD frequency: 0.00038  dbSNP: rs367855115

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000377002	SCV000336703	uncertain significance	not provided	2018-01-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000377002	SCV002542006	uncertain significance	not provided	2021-07-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002379123	SCV002695654	uncertain significance	Cardiovascular phenotype	2024-09-23	criteria provided, single submitter	clinical testing	The p.L320F variant (also known as c.958C>T), located in coding exon 5 of the CYP27A1 gene, results from a C to T substitution at nucleotide position 958. The leucine at codon 320 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518912	SCV003253387	uncertain significance	Cholestanol storage disease	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 320 of the CYP27A1 protein (p.Leu320Phe). This variant is present in population databases (rs367855115, gnomAD 0.1%). 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: 284184). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP27A1 protein function. 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.
GeneDx	RCV000377002	SCV003923981	uncertain significance	not provided	2024-12-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003947874	SCV004763311	uncertain significance	CYP27A1-related disorder	2023-12-13	no assertion criteria provided	clinical testing	The CYP27A1 c.958C>T variant is predicted to result in the amino acid substitution p.Leu320Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD, which is likely too common for an unreported disease-causing variant. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.