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

gnomAD frequency: 0.00001  dbSNP: rs201346271

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000056130	SCV001229364	pathogenic	Cholestanol storage disease	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 216 of the CYP27A1 protein (p.Ala216Pro). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs201346271, gnomAD 0.006%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 8827518, 10775536, 14999499, 24746394). This variant is also known as p.Ala183Pro. ClinVar contains an entry for this variant (Variation ID: 65885). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change alters CYP27A1 gene expression (PMID: 8827518). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
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 Center for Human Genetics Tuebingen	RCV001268441	SCV001502385	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	CYP27A1: PM3:Very Strong, PM2, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056130	SCV001983522	pathogenic	Cholestanol storage disease	2021-09-13	criteria provided, single submitter	clinical testing	Variant summary: CYP27A1 c.646G>C (p.Ala216Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant is located at the last nucleotide of exon 3. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. Four predict the variant abolishes a 3' acceptor site. Experimental studies report this variant to affect mRNA splicing (Garuti_1996). The variant allele was found at a frequency of 3.2e-05 in 251286 control chromosomes. c.646G>C has been reported in the literature in numerous individuals affected with Cerebrotendinous Xanthomatosis both in the homozygous and compound heterozygous state (Garuti_1996, Bartholdi_2004, Ginanneschi_2013, etc). Experimental studies performed on fibroblasts from an individual homozygous for the variant showed a negligible or a very low residual activity compared to controls (Garuti_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000056130	SCV002776778	pathogenic	Cholestanol storage disease	2021-12-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000056130	SCV004192675	pathogenic	Cholestanol storage disease	2023-08-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003964910	SCV004781174	pathogenic	CYP27A1-related condition	2023-11-15	criteria provided, single submitter	clinical testing	The CYP27A1 c.646G>C variant is predicted to result in the amino acid substitution p.Ala216Pro. This variant is also referred to as p.Ala183Pro in literature. This variant has been reported in the homozygous state and along with another variant in CYP27A1 in multiple individuals with cerebrotendinous xanthomatosis (Garuti et al. 1996. PubMed ID: 8827518, Gupta et al. 2007. PubMed ID: 17697869; Verrips et al. 2000. PubMed ID: 10775536). Splicing analysis found this variant results in aberrant splicing and reduced mRNA levels (Garuti et al. 1996. PubMed ID: 8827518; Gupta et al. 2007. PubMed ID: 17697869). This variant is interpreted as pathogenic.
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
Clinical Genetics, Academic Medical Center	RCV001268441	SCV001917630	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001268441	SCV001930560	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001268441	SCV001956543	pathogenic	not provided		no assertion criteria provided	clinical testing