ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.666_678del (p.Phe222fs) (rs755532803)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000598773 SCV000703385 pathogenic not provided 2017-11-06 criteria provided, single submitter clinical testing
GeneDx RCV000598773 SCV000710674 likely pathogenic not provided 2018-02-23 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the CYP27A1 gene. The c.666_678del13 variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.666_678del13 variant causes a frameshift starting with codon Phenylalanine 222, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Phe222LeufsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.666_678del13 variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000595702 SCV000754982 pathogenic Cholestanol storage disease 2018-08-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe222Leufs*13) in the CYP27A1 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with CYP27A1-related disease. Loss-of-function variants in CYP27A1 are known to be pathogenic (PMID: 9392430, 10775536, 26937392). For these reasons, this variant has been classified as Pathogenic.

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