VCV002690960.2 - ClinVar

NM_004959.5(NR5A1):c.593C>T (p.Pro198Leu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004959.5(NR5A1):c.593C>T (p.Pro198Leu)

Variation ID: 2690960 Accession: VCV002690960.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q33.3 9: 124500367 (GRCh38) [ NCBI UCSC ] 9: 127262646 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 29, 2024	Oct 26, 2024	Apr 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004959.5:c.593C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004950.2:p.Pro198Leu	missense
NM_004959.4:c.593C>T
NC_000009.12:g.124500367G>A
NC_000009.11:g.127262646G>A
NG_008176.1:g.12054C>T

... more HGVS ... less HGVS

Protein change

P198L

Other names

Canonical SPDI

NC_000009.12:124500366:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NR5A1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	265	297

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
46,XY disorder of sex development Oligosynaptic infertility	Uncertain significance (1)	criteria provided, single submitter	Jul 3, 2023	RCV003779265.2
Male infertility with azoospermia or oligozoospermia due to single gene mutation	Likely pathogenic (1)	criteria provided, single submitter	Sep 1, 2023	RCV003991621.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Apr 9, 2024	RCV004765860.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Sep 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Male infertility with azoospermia or oligozoospermia due to single gene mutation (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Laan Lab, Human Genetics Research Group, University of Tartu Accession: SCV004239164.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: DOI: 10.1016/j.ajhg.2024.03.013 DOI: 10.1016/j.ajhg.2024.03.013 Sex: male
Uncertain significance (Jul 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	46,XY disorder of sex development Oligosynaptic infertility Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004586041.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 23543655‚ 22100173 Comment: 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 … (more) 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. Experimental studies have shown that this missense change does not substantially affect NR5A1 function (PMID: 23543655). 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. This missense change has been observed in individual(s) with primary ovarian insufficiency (PMID: 22100173, 23543655). This variant is present in population databases (rs774216266, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 198 of the NR5A1 protein (p.Pro198Leu). (less)
Uncertain significance (Apr 09, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005376863.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional study demonstrated no effect on protein function (PMID: … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional study demonstrated no effect on protein function (PMID: 23543655); Identified in a patient with primary ovarian insufficiency, but it is unknown whether this individual was tested for variants in other genes associated with primary ovarian insufficiency (PMID: 22100173); This variant is associated with the following publications: (PMID: 23543655, 22100173, 36901862) (less)

Comment:

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. Experimental studies have shown that this missense change does not substantially affect NR5A1 function (PMID: 23543655). 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. This missense change has been observed in individual(s) with primary ovarian insufficiency (PMID: 22100173, 23543655). This variant is present in population databases (rs774216266, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 198 of the NR5A1 protein (p.Pro198Leu).

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional study demonstrated no effect on protein function (PMID: 23543655); Identified in a patient with primary ovarian insufficiency, but it is unknown whether this individual was tested for variants in other genes associated with primary ovarian insufficiency (PMID: 22100173); This variant is associated with the following publications: (PMID: 23543655, 22100173, 36901862)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Toward clinical exomes in diagnostics and management of male infertility.	Lillepea K	American journal of human genetics	2024	DOI: 10.1016/j.ajhg.2024.03.013
NR5A1 (SF-1) mutations are not a major cause of primary ovarian insufficiency.	Voican A	The Journal of clinical endocrinology and metabolism	2013	PMID: 23543655
Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI).	Janse F	Fertility and sterility	2012	PMID: 22100173

Text-mined citations for this variant ...

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_004959.5(NR5A1):c.593C>T (p.Pro198Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...