Submissions for variant NM_000475.5(NR0B1):c.516G>A (p.Trp172Ter)

dbSNP: rs1555973131

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540337	SCV000632386	pathogenic	Congenital adrenal hypoplasia, X-linked; 46,XY sex reversal 2	2023-09-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp172*) in the NR0B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NR0B1 are known to be pathogenic (PMID: 7990958, 15841486). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital adrenal hypoplasia (PMID: 7990958). ClinVar contains an entry for this variant (Variation ID: 460310). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375576	SCV001572471	pathogenic	Congenital adrenal hypoplasia, X-linked	2021-04-09	criteria provided, single submitter	clinical testing	Variant summary: NR0B1 c.516G>A (p.Trp172X) 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. Truncations around- and downstream of this position have been reported in affected individuals (HGMD). The variant was absent in 166051 control chromosomes (gnomAD). c.516G>A has been reported in the literature in at least two families, with multiple male individuals affected with X-Linked Adrenal Hypoplasia Congenita (AHC) (Muscatelli_1994, Merke_1999). One of these reports also described an unaffected male family member with the variant (grandfather), and an apparently homozygous female (aunt) affected with isolated hypogonadotropic hypogonadism (without AHC) that might suggest variable penetrance for the variant, however somatic mosaicism was also not entirely ruled out in this study (Merke_1999). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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.
GeneDx	RCV004592561	SCV005081100	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7990958)