Variant rs397515356 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000784.4(CYP27A1):c.944_948del(p.Leu315GlnfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CYP27A1
NM_000784.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.80

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 2-218813021-ACTGGC-A is Pathogenic according to our data. Variant chr2-218813021-ACTGGC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP27A1	NM_000784.4 linkuse as main transcript	c.944_948del	p.Leu315GlnfsTer15	frameshift_variant	5/9	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9 linkuse as main transcript	c.944_948del	p.Leu315GlnfsTer15	frameshift_variant	5/9	1	NM_000784.4	ENSP00000258415	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251348

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461888

Hom.:

AF XY:

0.00000413

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cholestanol storage disease

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 25, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 22, 2017	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 01, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This sequence change creates a premature translational stop signal (p.Leu315Glnfs*15) 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 (rs770589184, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of cerebrotendinous xanthomatosis (PMID: 12000359). This variant is also known as a five nucleotide deletion (TGGCC; nucleotides 965‚Äì969 of the cDNA). ClinVar contains an entry for this variant (Variation ID: 4265). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 05, 2018

- -

CYP27A1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2024

The CYP27A1 c.944_948del5 variant is predicted to result in a frameshift and premature protein termination (p.Leu315Glnfs*15). This variant has been reported in at least one individual with autosomal recessive cerebrotendinous xanthomatosis (reported as five-nucleotide deletion in Figure 2, Lamon-Fava et al. 2002. PubMed ID: 12000359; Nóbrega et al. 2022. PubMed ID: 36619921). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. Frameshift variants in CYP27A1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2021

The c.944_948delTGGCC (p.L315Qfs*15) alteration, located in exon 5 (coding exon 5) of the CYP27A1 gene, consists of a deletion of 5 nucleotides from position 944 to 948, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant (referred to as a five nucleotide deletion of TGGCC) co-occurred with a second variant in CYP27A1 gene in an individual reported to have cerebrotendinous xanthomatosis (Lamon-Fava, 2002) Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over