NM_004959.5(NR5A1):c.274C>T (p.Arg92Trp) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 16, 2021
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:: RCV001855015.5

Allele description [Variation Report for NM_004959.5(NR5A1):c.274C>T (p.Arg92Trp)]

NM_004959.5(NR5A1):c.274C>T (p.Arg92Trp)

Gene:

NR5A1:nuclear receptor subfamily 5 group A member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q33.3

Genomic location:

Preferred name:

NM_004959.5(NR5A1):c.274C>T (p.Arg92Trp)

HGVS:

NC_000009.12:g.124500686G>A
NG_008176.1:g.11735C>T
NM_004959.5:c.274C>TMANE SELECT
NP_004950.2:p.Arg92Trp
NC_000009.11:g.127262965G>A
NM_004959.4:c.274C>T
p.R92W

Protein change:

R92W; ARG92TRP

Links:

OMIM: 184757.0019; dbSNP: rs886039769

NCBI 1000 Genomes Browser:

rs886039769

Molecular consequence:

NM_004959.5:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Oligosynaptic infertility (SPGF1)
Synonyms:: SPERMATOGENIC FAILURE 1; OLIGOCHIASMATIC INFERTILITY
Identifiers:: MONDO: MONDO:0009776; MedGen: C0403810; OMIM: 258150

Name:: 46,XY disorder of sex development
Synonyms:: 46, XY disorder of sex development (DSD)
Identifiers:: MONDO: MONDO:0020040; MedGen: C2751824

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002243305	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 16, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27490115, 28033660, 27378692, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002243305

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 16, 2021)

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

NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.

Baetens D, Stoop H, Peelman F, Todeschini AL, Rosseel T, Coppieters F, Veitia RA, Looijenga LH, De Baere E, Cools M.

Genet Med. 2017 Apr;19(4):367-376. doi: 10.1038/gim.2016.118. Epub 2016 Aug 4.

PubMed [citation]

PMID:: 27490115
PMCID:: PMC5392598

Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals.

Domenice S, Machado AZ, Ferreira FM, Ferraz-de-Souza B, Lerario AM, Lin L, Nishi MY, Gomes NL, da Silva TE, Silva RB, Correa RV, Montenegro LR, Narciso A, Costa EM, Achermann JC, Mendonca BB.

Birth Defects Res C Embryo Today. 2016 Dec;108(4):309-320. doi: 10.1002/bdrc.21145. Review.

PubMed [citation]

PMID:: 28033660
PMCID:: PMC5347970

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002243305.3

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

Description

ClinVar contains an entry for this variant (Variation ID: 265792). This missense change has been observed in individual(s) with NR5A1-related conditions (PMID: 27378692, 27490115, 28033660). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 92 of the NR5A1 protein (p.Arg92Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NR5A1 function (PMID: 27378692).

#	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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