12-57763698-T-TGGGTGGG

Position:

• chr12-57763698-T-TGGGTGGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000785.4(CYP27B1):​c.1319_1325dupCCCACCC​(p.Phe443fs) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP27B1 NM_000785.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 6.83

Genes affected

CYP27B1 (HGNC:2606): (cytochrome P450 family 27 subfamily B 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. The protein encoded by this gene localizes to the inner mitochondrial membrane where it hydroxylates 25-hydroxyvitamin D3 at the 1alpha position. This reaction synthesizes 1alpha,25-dihydroxyvitamin D3, the active form of vitamin D3, which binds to the vitamin D receptor and regulates calcium metabolism. Thus this enzyme regulates the level of biologically active vitamin D and plays an important role in calcium homeostasis. Mutations in this gene can result in vitamin D-dependent rickets type I. [provided by RefSeq, Jul 2008]

CYP27B1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.132 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PP5: Variant 12-57763698-T-TGGGTGGG is Pathogenic according to our data. Variant chr12-57763698-T-TGGGTGGG is described in ClinVar as [Pathogenic]. Clinvar id is 279798.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
CYP27B1	NM_000785.4	c.1319_1325dupCCCACCC	p.Phe443fs	frameshift_variant	8/9	ENST00000228606.9	NP_000776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP27B1	ENST00000228606.9	c.1319_1325dupCCCACCC	p.Phe443fs	frameshift_variant	8/9	1	NM_000785.4	ENSP00000228606.4
CYP27B1	ENST00000547344.5	n.1458_1464dupCCCACCC		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 26 AN: 149740 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.0000491

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000994

Gnomad SAS AF: 0.000429

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000193

Gnomad OTH AF: 0.000487

GnomAD3 exomes AF: 0.000223 AC: 56 AN: 251182 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135890

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000213 AC: 298 AN: 1400382 Hom.: 0 Cov.: 38 AF XY: 0.000190 AC XY: 133 AN XY: 699120

Gnomad4 AFR exome AF: 0.000186

Gnomad4 AMR exome AF: 0.000405

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.000206

Gnomad4 SAS exome AF: 0.000188

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000222

Gnomad4 OTH exome AF: 0.000224

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000174 AC: 26 AN: 149854 Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 8 AN XY: 73186

Gnomad4 AFR AF: 0.0000490

Gnomad4 AMR AF: 0.000199

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000997

Gnomad4 SAS AF: 0.000429

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000193

Gnomad4 OTH AF: 0.000482

Alfa AF: 0.000144 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vitamin D-dependent rickets, type 1A Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 18, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2024	Variant summary: CYP27B1 c.1319_1325dupCCCACCC (p.Phe443ProfsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 0.00022 in 251182 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CYP27B1 causing Vitamin D-dependent rickets (0.00022 vs 0.0011), allowing no conclusion about variant significance. c.1319_1325dupCCCACCC has been reported in the literature in multiple individuals affected with Vitamin D-dependent rickets (example: Kaygusuz_2021). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 33386952). ClinVar contains an entry for this variant (Variation ID: 279798). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Payam Genetics Center, General Welfare Department of North Khorasan Province	Mar 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Jan 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant was co-segregated with Vitamin D-dependent rickets, type I in multiple affected family members (PMID: 22443290, PP1_P). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000279798, PMID:9837822). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000209, PM2_M). The variant has been reported to be in trans as homozygous in at least one similarly affected unrelated individual (PMID: 22443290,PM3_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Nov 04, 2022	PVS1, PM2, PP5 -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2022	Frameshift variant predicted to result in protein truncation, as the last 66 amino acids are replaced with 23 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 9837822, 22443290, 28587998, 22588163, 31980526, 25296067, 31589614, 33386952, 33004071, 25284246, 30282619, 33329754) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Dec 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Phe443Profs*24) in the CYP27B1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the CYP27B1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with vitamin D-dependent rickets (PMID: 9837822, 22443290, 25296067). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1325-1326insCCCACCC and 7bpdup. ClinVar contains an entry for this variant (Variation ID: 279798). 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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2021

The c.1319_1325dupCCCACCC (p.F443Pfs*24) alteration, located in coding exon 8 of the CYP27B1 gene, consists of a duplication of 7 nucleotides at position 1319, causing a translational frameshift with a predicted alternate stop codon after 24 amino acids. This alteration occurs at the 3' terminus of the CYP27B1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 12.8% (65/508 amino acids) of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). The p.F443Pfs*24 alteration has been reported in both a homozygous and compound heterozygous state with other alterations in the CYP27B1 gene in several unrelated patients with vitamin D-dependent rickets (Wang, 1998; Durmaz, 2012; Ito, 2014; Dursun, 2019; Li, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

CYP27B1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2024

The CYP27B1 c.1319_1325dup7 variant is predicted to result in a frameshift and premature protein termination (p.Phe443Profs*24). This variant in the compound heterozygous and homozygous conditions was repeatedly reported to be pathogenic for pseudo–vitamin D–deficiency rickets (see example: reported as c.1325-1326insCCCACCC, Ito et al. 2014. PubMed ID: 25296067; Durmaz. 2012. PubMed ID: 22443290). This variant is reported in 0.045% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in CYP27B1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Vitamin D-dependent rickets, type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Feb 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs780950819; hg19: chr12-58157481;