VCV000981141.5 - ClinVar

NM_004959.5(NR5A1):c.1063G>A (p.Val355Met)

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(2); Uncertain significance(1)

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.1063G>A (p.Val355Met)

Variation ID: 981141 Accession: VCV000981141.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q33.3 9: 124491156 (GRCh38) [ NCBI UCSC ] 9: 127253435 (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	Jan 15, 2023	Mar 16, 2024	Jan 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004959.5:c.1063G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004950.2:p.Val355Met	missense
NC_000009.12:g.124491156C>T
NC_000009.11:g.127253435C>T
NG_008176.1:g.21265G>A

Protein change

V355M

Other names

Canonical SPDI

NC_000009.12:124491155:C:T

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.
Premature ovarian failure 7	Likely pathogenic (1)	criteria provided, single submitter	Jan 3, 2023	RCV002509643.1
46,XY disorder of sex development Oligosynaptic infertility	Uncertain significance (1)	criteria provided, single submitter	May 15, 2022	RCV002537605.3
Male infertility	Likely pathogenic (1)	criteria provided, single submitter	Jan 16, 2024	RCV003983865.2

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 (Jan 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Premature ovarian failure 7 (Sporadic) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Goettingen Accession: SCV002817383.1 First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023	Sex: female
Uncertain significance (May 15, 2022)	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: SCV003026220.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 17940071‚ 32655042‚ 30067310 Comment: This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 355 of the NR5A1 protein (p.Val355Met). … (more) This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 355 of the NR5A1 protein (p.Val355Met). This variant is present in population databases (rs371701248, gnomAD 0.03%). This missense change has been observed in individual(s) with anorchia or idiopathic oligozoospermia (PMID: 17940071, 32655042). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NR5A1 function (PMID: 17940071, 30067310). 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. (less)
Likely pathogenic (Jan 16, 2024)	criteria provided, single submitter (Uk Practice Guidelines For Variant Classification V4 01 2020) Method: research, in vitro	Male infertility Affected status: not applicable, unknown Allele origin: germline, not applicable	Institute of Reproductive Genetics, University of Münster Accession: SCV004800827.1 First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024	Observation 1: Number of individuals with the variant: 1 Clinical Features: Azoospermia (present) Secondary finding: no Observation 2: Method: Dual-luciferase reporter assays Result: normal transcriptional activity

Comment:

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 355 of the NR5A1 protein (p.Val355Met). This variant is present in population databases (rs371701248, gnomAD 0.03%). This missense change has been observed in individual(s) with anorchia or idiopathic oligozoospermia (PMID: 17940071, 32655042). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NR5A1 function (PMID: 17940071, 30067310). 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.

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
Next-generation sequencing: toward an increase in the diagnostic yield in patients with apparently idiopathic spermatogenic failure.	Cannarella R	Asian journal of andrology	2021	PMID: 32655042
Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer.	Sreenivasan R	Human mutation	2018	PMID: 30067310
Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study.	Philibert P	Human reproduction (Oxford, England)	2007	PMID: 17940071

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004959.5(NR5A1):c.1063G>A (p.Val355Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...