NM_000785.4(CYP27B1):c.262del (p.Val88fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000254925.5

Allele description [Variation Report for NM_000785.4(CYP27B1):c.262del (p.Val88fs)]

NM_000785.4(CYP27B1):c.262del (p.Val88fs)

Gene:

CYP27B1:cytochrome P450 family 27 subfamily B member 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

12q14.1

Genomic location:

Preferred name:

NM_000785.4(CYP27B1):c.262del (p.Val88fs)

HGVS:

NC_000012.12:g.57766131del
NG_007076.1:g.6063del
NM_000785.4:c.262delMANE SELECT
NP_000776.1:p.Val88fs
NC_000012.11:g.58159914del
NM_000785.3:c.262del
NM_000785.3:c.262delG

Protein change:

V88fs

Links:

OMIM: 609506.0007; dbSNP: rs387906260

NCBI 1000 Genomes Browser:

rs387906260

Molecular consequence:

NM_000785.4:c.262del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321541	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 22, 2023)	germline	clinical testing	Citation Link,
SCV004294216	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9837822, 17488797, 25086671, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000321541

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 22, 2023)

germline

clinical testing

Citation Link,

SCV004294216

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families.

Wang JT, Lin CJ, Burridge SM, Fu GK, Labuda M, Portale AA, Miller WL.

Am J Hum Genet. 1998 Dec;63(6):1694-702.

PubMed [citation]

PMID:: 9837822
PMCID:: PMC1377641

Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency.

Kim CJ, Kaplan LE, Perwad F, Huang N, Sharma A, Choi Y, Miller WL, Portale AA.

J Clin Endocrinol Metab. 2007 Aug;92(8):3177-82. Epub 2007 May 8.

PubMed [citation]

PMID:: 17488797

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000321541.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Common recurring hotspot deletion that has been reported previously in association with vitamin D-dependent rickets (VDDR type 1; also known as pseudo vitamin D deficiency rickets and vitamin D 1-alpha hydroxylase deficiency); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25086671, 1937486, 9837822, 16143014, 9844119, 35600579)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004294216.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Val88Trpfs*71) in the CYP27B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP27B1 are known to be pathogenic (PMID: 9837822, 17488797). This variant is present in population databases (rs387906260, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with vitamin D-dependent rickets (PMID: 25086671). ClinVar contains an entry for this variant (Variation ID: 1664). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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