ClinVar Miner

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

gnomAD frequency: 0.00013  dbSNP: rs121908102
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Total submissions: 17
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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 Inc 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
Invitae RCV000004487 SCV001205735 pathogenic Cholestanol storage disease 2021-12-01 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
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 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)
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
PerkinElmer Genomics RCV000004487 SCV002018121 pathogenic Cholestanol storage disease 2019-09-06 no assertion criteria provided clinical testing

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