Submissions for variant NM_000785.4(CYP27B1):c.171dup (p.Leu58fs)

dbSNP: rs763437121

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000731471	SCV000859293	pathogenic	not provided	2018-01-19	criteria provided, single submitter	clinical testing
Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi	RCV001843547	SCV002102807	pathogenic	Vitamin D-dependent rickets, type 1A	2022-03-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000731471	SCV002194611	pathogenic	not provided	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu58Alafs*275) 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). 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 individual(s) with vitamin D-dependent rickets (PMID: 31261480). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 595816). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001843547	SCV005849034	pathogenic	Vitamin D-dependent rickets, type 1A	2023-06-22	criteria provided, single submitter	clinical testing	The frameshift c.171dup(p.Leu58AlafsTer275) variant in CYP27B1 gene has been reported in compound heterozygous/ homozygous states in individual(s) affected with Vitamin D-Dependent Rickets (Kim YM, et. al., 2019; Zou M, et. al., 2020). This variant is present with an allele frequency of 0.0008% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Leucine 58, changes this amino acid to Alanine residue, and creates a premature Stop codon at position 275 of the new reading frame, denoted p.Leu58AlafsTer275. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Kim CJ, et. al., 2007). For these reasons, this variant has been classified as Pathogenic.