chr2-218809688-AAGTACCC-A

Variant names:

• chr2-218809688-AAGTACCC-A
• rs587778794
• NM_000784.4:c.373_379delCCAGTAC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000784.4(CYP27A1):​c.373_379delCCAGTAC​(p.Pro125GlyfsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P125P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CYP27A1 NM_000784.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.90
• Publications: 2 publications found

Genes affected

CYP27A1 (HGNC:2605): (cytochrome P450 family 27 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This mitochondrial protein oxidizes cholesterol intermediates as part of the bile synthesis pathway. Since the conversion of cholesterol to bile acids is the major route for removing cholesterol from the body, this protein is important for overall cholesterol homeostasis. Mutations in this gene cause cerebrotendinous xanthomatosis, a rare autosomal recessive lipid storage disease. [provided by RefSeq, Jul 2008]

CYP27A1 Gene-Disease associations (from GenCC):

• cerebrotendinous xanthomatosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-218809688-AAGTACCC-A is Pathogenic according to our data. Variant chr2-218809688-AAGTACCC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 65864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.373_379delCCAGTAC	p.Pro125GlyfsTer16	frameshift_variant	Exon 2 of 9	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9	c.373_379delCCAGTAC	p.Pro125GlyfsTer16	frameshift_variant	Exon 2 of 9	1	NM_000784.4	ENSP00000258415.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251418 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cholestanol storage disease Pathogenic:3

Feb 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Pro125Glyfs*16) in the CYP27A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP27A1 are known to be pathogenic (PMID: 9392430, 10775536, 26937392). This variant is present in population databases (rs587778794, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 22018287). This variant is also known as c.369_375delGTACCCA. ClinVar contains an entry for this variant (Variation ID: 65864). For these reasons, this variant has been classified as Pathogenic. -

Aug 01, 2013

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Feb 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=14/186	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587778794; hg19: chr2-219674411;