ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.646G>C (p.Ala216Pro) (rs201346271)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000056130 SCV001229364 pathogenic Cholestanol storage disease 2020-08-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 216 of the CYP27A1 protein (p.Ala216Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant also falls at the last nucleotide of exon 3 of the CYP27A1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs201346271, ExAC 0.004%). This variant has been observed to be homozygous or in combination with another CYP27A1 variant in individuals affected with cerebrotendinous xanthomatosis (PMID: 10775536, 14999499, 8827518, 24746394). This variant is also known as p.Ala183Pro in the literature. ClinVar contains an entry for this variant (Variation ID: 65885). 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). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 8827518). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268441 SCV001447376 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001268441 SCV001502385 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
GeneReviews RCV000056130 SCV000087208 pathologic Cholestanol storage disease 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000056130 SCV001455784 pathogenic Cholestanol storage disease 2020-09-16 no assertion criteria provided clinical testing

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