Submissions for variant NM_000784.4(CYP27A1):c.1016C>T (p.Thr339Met)

gnomAD frequency: 0.00013  dbSNP: rs121908102

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000004487	SCV000427475	pathogenic	Cholestanol storage disease	2017-04-27	criteria provided, single submitter	clinical testing	The CYP27A1 c.1016C>T (p.Thr339Met) variant has been reported in six studies in which it was found in a homozygous state in five individuals and in a compound heterozygous state in four individuals, all with cerebrotendinous xanthomatosis, and in a heterozygous state in four unaffected family members (Reshef et al. 1994; Guyant-Marechal et al. 2005; Pilo-de-la-Fuente et al. 2011; Caroppo et al. 2013; Schabhuttl et al. 2014; Huidekoper et al. 2016). The p.Thr339Met variant was absent from 100 controls and is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium. The Thr306 residue is conserved and located in the heme-binding site of the protein. Based on the evidence, the p.Thr339Met variant is classified as pathogenic for cerebrotendinous xanthomatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genetic Services Laboratory, University of Chicago	RCV000004487	SCV000594288	likely pathogenic	Cholestanol storage disease	2016-05-19	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000518366	SCV000613048	likely pathogenic	not provided	2017-05-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000004487	SCV000893577	pathogenic	Cholestanol storage disease	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000004487	SCV001136215	pathogenic	Cholestanol storage disease	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004487	SCV001205735	pathogenic	Cholestanol storage disease	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 339 of the CYP27A1 protein (p.Thr339Met). This variant is present in population databases (rs121908102, gnomAD 0.01%). This missense change has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 8014582, 24627108, 26156051, 27858369). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr306Met. ClinVar contains an entry for this variant (Variation ID: 4266). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CYP27A1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000518366	SCV001371651	pathogenic	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000004487	SCV002018121	pathogenic	Cholestanol storage disease	2023-05-25	criteria provided, single submitter	clinical testing
DASA	RCV000004487	SCV002061254	pathogenic	Cholestanol storage disease	2022-01-05	criteria provided, single submitter	clinical testing	The c.1016C>T;p.(Thr339Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID 4266; PMID: 27142713; 26156051; 24627108; 23212406; 16278884) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11737215) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Cytochrome P450 domain) - PM1. The variant is present at low allele frequencies population databases (rs121908102– gnomAD 0.001117%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Thr339Met) was detected in trans with a pathogenic variant (PMID: 27142713; 26156051; 24627108; 23212406; 16278884) - PM3_very strong Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
3billion, Medical Genetics	RCV000004487	SCV002521494	pathogenic	Cholestanol storage disease	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.74). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004266). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 24627108, 26156051, 27858369) and to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID:8014582). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV000518366	SCV002526584	pathogenic	not provided	2022-05-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate absent functional heme activity (Gupta et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16278884, 26643207, 21404287, 17697869, 11181744, 26156051, 28894950, 30270055, 21627786, 21645175, 23212406, 24627108, 27142713, 27858369, 8014582, 31589614, 33414089, 31796091)
Baylor Genetics	RCV000004487	SCV004192643	likely pathogenic	Cholestanol storage disease	2024-03-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000518366	SCV005413553	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PM2_moderate, PM3_very_strong
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000004487	SCV005418347	pathogenic	Cholestanol storage disease		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Strong+PM3_VeryStrong+PP4
OMIM	RCV000004487	SCV000024661	pathogenic	Cholestanol storage disease	2005-12-01	no assertion criteria provided	literature only
Counsyl	RCV000004487	SCV001132160	pathogenic	Cholestanol storage disease	2016-12-01	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000518366	SCV001739897	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000518366	SCV001922630	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000518366	SCV001957093	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000518366	SCV001964791	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003430633	SCV004118170	pathogenic	CYP27A1-related disorder	2023-11-29	no assertion criteria provided	clinical testing	The CYP27A1 c.1016C>T variant is predicted to result in the amino acid substitution p.Thr339Met. Using legacy nomenclature, this variant is also known in the literature as p.Thr306Met. This variant has been reported in several patients with cerebrotendinous xanthomatosis (Family #202 in Reshef et al 1994. PubMed ID: 8014582; Schabhüttl et al 2014. PubMed ID: 24627108; Guyant-Maréchal et al 2005. PubMed ID: 16278884; Huidekoper et al 2015. PubMed ID: 26156051). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and has been interpreted as pathogenic or likely pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4266). This variant is interpreted as pathogenic.