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

gnomAD frequency: 0.00004  dbSNP: rs387906260

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254925	SCV000321541	pathogenic	not provided	2023-03-22	criteria provided, single submitter	clinical testing	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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001731	SCV002600516	pathogenic	Vitamin D-dependent rickets, type 1A	2022-10-15	criteria provided, single submitter	clinical testing	Variant summary: CYP27B1 c.262delG (p.Val88TrpfsX71) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.5e-05 in 142666 control chromosomes. c.262delG has been reported in the literature in multiple individuals affected with features of Vitamin D-Dependent Rickets, Type 1 (example, Edouard_2011). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000254925	SCV004294216	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000001731	SCV005629944	pathogenic	Vitamin D-dependent rickets, type 1A	2024-05-16	criteria provided, single submitter	clinical testing
OMIM	RCV000001731	SCV000021887	pathogenic	Vitamin D-dependent rickets, type 1A	1998-12-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004755698	SCV005351677	pathogenic	CYP27B1-related disorder	2024-08-19	no assertion criteria provided	clinical testing	The CYP27B1 c.262delG variant is predicted to result in a frameshift and premature protein termination (p.Val88Trpfs*71). This variant was reported in the homozygous or compound heterozygous states in individuals with vitamin D-deficiency rickets type I, and this variant is suspected to be a founder mutation in French-Canadian population originating from the Charlevoix-Saguenay-Lac Saint Jean region (reported as 958delG, Wang et al. 1998. PubMed ID: 9837822; Kim et al. 2007. PubMed ID: 17488797). This variant is reported in 0.009% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CYP27B1 are expected to be pathogenic. This variant is interpreted as pathogenic.