NM_004959.5(NR5A1):c.712G>A (p.Asp238Asn) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 9, 2024
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:: RCV002538522.3

Allele description [Variation Report for NM_004959.5(NR5A1):c.712G>A (p.Asp238Asn)]

NM_004959.5(NR5A1):c.712G>A (p.Asp238Asn)

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.712G>A (p.Asp238Asn)

HGVS:

NC_000009.12:g.124500248C>T
NG_008176.1:g.12173G>A
NM_004959.5:c.712G>AMANE SELECT
NP_004950.2:p.Asp238Asn
NC_000009.11:g.127262527C>T
NM_004959.4:c.712G>A

Protein change:

D238N

Links:

dbSNP: rs780568525

NCBI 1000 Genomes Browser:

rs780568525

Molecular consequence:

NM_004959.5:c.712G>A - 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
SCV003309555	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 9, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 35690514, 20887963, 25989977, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003309555

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 9, 2024)

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

Genetic Architecture of Azoospermia-Time to Advance the Standard of Care.

Wyrwoll MJ, Köckerling N, Vockel M, Dicke AK, Rotte N, Pohl E, Emich J, Wöste M, Ruckert C, Wabschke R, Seggewiss J, Ledig S, Tewes AC, Stratis Y, Cremers JF, Wistuba J, Krallmann C, Kliesch S, Röpke A, Stallmeyer B, Friedrich C, Tüttelmann F.

Eur Urol. 2023 May;83(5):452-462. doi: 10.1016/j.eururo.2022.05.011. Epub 2022 Jun 8.

PubMed [citation]

PMID:: 35690514

Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1.

Bashamboo A, Ferraz-de-Souza B, Lourenço D, Lin L, Sebire NJ, Montjean D, Bignon-Topalovic J, Mandelbaum J, Siffroi JP, Christin-Maitre S, Radhakrishna U, Rouba H, Ravel C, Seeler J, Achermann JC, McElreavey K.

Am J Hum Genet. 2010 Oct 8;87(4):505-12. doi: 10.1016/j.ajhg.2010.09.009. Erratum in: Am J Hum Genet. 2010 Nov 12;87(5):736.

PubMed [citation]

PMID:: 20887963
PMCID:: PMC2948805

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003309555.2

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 238 of the NR5A1 protein (p.Asp238Asn). This variant is present in population databases (rs780568525, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of spermatogenic failure (PMID: 20887963, 25989977, 35690514). ClinVar contains an entry for this variant (Variation ID: 1244229). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NR5A1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NR5A1 function (PMID: 20887963, 25989977). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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