Submissions for variant NM_000784.4(CYP27A1):c.1184G>A (p.Arg395His)

gnomAD frequency: 0.00011  dbSNP: rs587778778

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000593893	SCV000709264	likely pathogenic	not provided	2017-06-13	criteria provided, single submitter	clinical testing
Invitae	RCV000056074	SCV001229624	pathogenic	Cholestanol storage disease	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 395 of the CYP27A1 protein (p.Arg395His). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587778778, gnomAD 0.04%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 8950197). This variant is also known as Arg362His. ClinVar contains an entry for this variant (Variation ID: 65834). 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. Experimental studies have shown that this missense change affects CYP27A1 function (PMID: 17697869). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 6 and activation of a cryptic splice site and introduces a premature termination codon (PMID: 9548584). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000593893	SCV001248937	pathogenic	not provided	2018-01-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000056074	SCV002018122	pathogenic	Cholestanol storage disease	2021-07-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000056074	SCV002060391	likely pathogenic	Cholestanol storage disease	2021-11-03	criteria provided, single submitter	clinical testing	NM_000784.3(CYP27A1):c.1184G>A(R395H) is a missense variant classified as likely pathogenic in the context of cerebrotendinous xanthomatosis. R395H has been observed in cases with relevant disease (PMID: 11181744, 8950197). Functional assessments of this variant are available in the literature (PMID 7697869, 8950197, 9548584). R395H has been observed in population frequency databases (gnomAD: ASJ 0.06%). In summary, NM_000784.3(CYP27A1):c.1184G>A(R395H) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
GeneDx	RCV000593893	SCV003933228	likely pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, as the variant leads to aberrant splicing and a non-functional enzyme (Chen et al., 1998); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32344004, 34689324, 16816916, 33704661, 17697869, 11181744, 8950197, 9521761, 27175728, 26643207, 9548584)
Baylor Genetics	RCV000056074	SCV004192667	likely pathogenic	Cholestanol storage disease	2023-09-20	criteria provided, single submitter	clinical testing
GeneReviews	RCV000056074	SCV000087139	pathologic	Cholestanol storage disease	2013-08-01	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Natera, Inc.	RCV000056074	SCV002078802	pathogenic	Cholestanol storage disease	2020-01-20	no assertion criteria provided	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000056074	SCV002573718	likely pathogenic	Cholestanol storage disease		no assertion criteria provided	clinical testing