NM_000475.5(NR0B1):c.1292del (p.Ser431fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 22, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003064681.3

Allele description [Variation Report for NM_000475.5(NR0B1):c.1292del (p.Ser431fs)]

NM_000475.5(NR0B1):c.1292del (p.Ser431fs)

Gene:

NR0B1:nuclear receptor subfamily 0 group B member 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

Xp21.2

Genomic location:

Preferred name:

NM_000475.5(NR0B1):c.1292del (p.Ser431fs)

HGVS:

NC_000023.11:g.30304700del
NG_009814.1:g.9679del
NM_000475.5:c.1292delMANE SELECT
NP_000466.2:p.Ser431fs
LRG_858t1:c.1292del
LRG_858:g.9679del
LRG_858p1:p.Ser431fs
NC_000023.10:g.30322817del

Protein change:

S431fs

Molecular consequence:

NM_000475.5:c.1292del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Congenital adrenal hypoplasia, X-linked (AHC)
Synonyms:: ADRENAL HYPOPLASIA, CONGENITAL, WITH HYPOGONADOTROPIC HYPOGONADISM; X-linked AHC; Adrenal hypoplasia, congenital; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010264; MedGen: C0342482; OMIM: 300200

Name:: 46,XY sex reversal 2
Synonyms:: Dosage-sensitive sex reversal; 46,XY SEX REVERSAL, DAX1-RELATED; NR0B1-Related 46,XY CGD; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010226; MedGen: C1848296; OMIM: 300018

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003444479	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 22, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22761912, 7609262, 26500747, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003444479

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 22, 2022)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Longitudinal evaluation of the hypothalamic-pituitary-testicular function in 8 boys with adrenal hypoplasia congenita (AHC) due to NR0B1 mutations.

Galeotti C, Lahlou Z, Goullon D, Sarda-Thibault H, Cahen-Varsaux J, Bignon-Topalovic J, Bashamboo A, McElreavey K, Brauner R.

PLoS One. 2012;7(6):e39828. doi: 10.1371/journal.pone.0039828. Epub 2012 Jun 27.

PubMed [citation]

PMID:: 22761912
PMCID:: PMC3384599

Diagnosis of X-linked adrenal hypoplasia congenita by mutation analysis of the DAX1 gene.

Guo W, Mason JS, Stone CG Jr, Morgan SA, Madu SI, Baldini A, Lindsay EA, Biesecker LG, Copeland KC, Horlick MN, et al.

JAMA. 1995 Jul 26;274(4):324-30.

PubMed [citation]

PMID:: 7609262

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003444479.2

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NR0B1 protein in which other variant(s) (p.Ile439Glnfs*5) have been observed in individuals with NR0B1-related conditions (PMID: 22761912). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individuals with X-linked adrenal hypoplasia (PMID: 7609262, 26500747). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser431Ilefs*6) in the NR0B1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the NR0B1 protein.

#	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: Sep 29, 2024

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