rs765512351

chr2-218812299-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000784.4(CYP27A1):c.526del(p.Asp176MetfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T175T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CYP27A1 NM_000784.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: -6.34

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 2-218812299-CG-C is Pathogenic according to our data. Variant chr2-218812299-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 334367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP27A1	NM_000784.4	c.526del	p.Asp176MetfsTer6	frameshift_variant	3/9	ENST00000258415.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP27A1	ENST00000258415.9	c.526del	p.Asp176MetfsTer6	frameshift_variant	3/9	1	NM_000784.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251472 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461830 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cholestanol storage disease Pathogenic:9

Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 21, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CYP27A1 c.525delG (p.Asp176MetfsTer6) variant, also known as c.526delG, results in a frameshift, and is predicted to result in premature termination of the protein. The p.Asp176MetfsTer6 variant has been reported in four studies in which it is found in a total of five individuals with cerebrotendinous xanthomatosis, including two siblings, all of whom were homozygous for the variant (Verrips et al. 1996; Clayton et al. 2002; Shah et al. 2012; Dutta et al. 2015). The variant has also been reported in a heterozygous state in one unaffected individual. Control data are unavailable for this variant which is reported at a frequency of 0.00012 in the South Asian population of the Exome Aggregation Consortium, but this is based on two alleles only in a region of good sequence coverage so the variant is presumed rare. Due to the potential impact of frameshift variants and the supporting evidence from the literature, the p.Asp176MetfsTer6 variant is classified as likely pathogenic for cerebrotendinous xanthomatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	This variant causes a frameshift starting with codon Aspartic Acid 176, changes this amino acid to Methionine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Asp176MetfsTer6. This variant has been previously reported in affected patients and has segregated with disease (Dutta AK et al, Shah K et al, Clayton PT et al). The variant has been reported to ClinVar as Pathogenic. The p.Asp176MetfsTer6 variant is novel (not in any individuals) in 1000 Genomes and is present at a frequency of 0.00012 in South Asian population in the gnomad database. The variant is predicted to cause loss of function due to protein truncation. Loss of function variants have been previously reported to be disease causing. Hence the above variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 19, 2023	This sequence change creates a premature translational stop signal (p.Asp176Metfs*6) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 334367). This variant is also known as c.546del. This premature translational stop signal has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 8931710, 26937392). This variant is present in population databases (rs765512351, gnomAD 0.03%). -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 19, 2021	- -

CYP27A1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 22, 2022

The CYP27A1 c.526delG variant is predicted to result in a frameshift and premature protein termination (p.Asp176Metfs*6). This variant was reported in the homozygous state in individuals with cerebrotendinous xanthomatosis (reported as G deletion at position 546 or 547 in Verrips et al. 1996. PubMed ID: 8931710; Dutta et al. 2015. PubMed ID: 26937392). This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219677022-CG-C). Frameshift variants in CYP27A1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs765512351; hg19: chr2-219677022;