VCV000010794.44 - ClinVar

NM_024921.4(POF1B):c.986G>A (p.Arg329Gln)

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.

(8)

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(4); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024921.4(POF1B):c.986G>A (p.Arg329Gln)

Variation ID: 10794 Accession: VCV000010794.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq21.1 X: 85308188 (GRCh38) [ NCBI UCSC ] X: 84563194 (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	May 13, 2017	Apr 15, 2024	Apr 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024921.4:c.986G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079197.3:p.Arg329Gln	missense
NM_001307940.2:c.986G>A	NP_001294869.1:p.Arg329Gln	missense
NC_000023.11:g.85308188C>T
NC_000023.10:g.84563194C>T
NG_016358.1:g.76555G>A
	Q8WVV4:p.Arg329Gln

... more HGVS ... less HGVS

Protein change

R329Q

Other names

Canonical SPDI

NC_000023.11:85308187: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.

0.00291 (T)

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

1000 Genomes Project 30x 0.00271

The Genome Aggregation Database (gnomAD), exomes 0.00271

Exome Aggregation Consortium (ExAC) 0.00272

1000 Genomes Project 0.00291

The Genome Aggregation Database (gnomAD) 0.00354

Trans-Omics for Precision Medicine (TOPMed) 0.00458

Links

ClinGen: CA121177 UniProtKB: Q8WVV4#VAR_028757 OMIM: 300603.0001 dbSNP: rs75398746 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.
POF1B		-	-	GRCh38 GRCh37	82	246

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 2B	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Apr 4, 2024	RCV000011541.24
Premature ovarian insufficiency	Uncertain significance (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626964.4
not provided	Benign (1)	criteria provided, single submitter	Jun 15, 2018	RCV000953408.4

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.
Benign (Jun 15, 2018)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001099981.1 First in ClinVar: Dec 17, 2019 Last updated: Dec 17, 2019
Uncertain significance (Mar 19, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Premature ovarian failure 2B Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003809129.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Premature ovarian insufficiency Premature ovarian insufficiency Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747667.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Likely pathogenic (Mar 26, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Premature ovarian failure 2B Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915304.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (4) PubMed: 25676666‚ 21940798‚ 16773570‚ 15459172 Comment: Lacombe et al. (2006) identified the POF1B c.986G>A (p.Arg329Gln) variant in a homozygous state in five sisters with POF from a consanguineous Lebanese family. The … (more) Lacombe et al. (2006) identified the POF1B c.986G>A (p.Arg329Gln) variant in a homozygous state in five sisters with POF from a consanguineous Lebanese family. The variant was also identified in a heterozygous state in the unaffected mother and an unaffected sister. The p.Arg329Gln variant has also been reported in two additional patients with POF, including in a heterozygous state in one patient with a second unidentified variant and in one patient with the p.Arg329Gln variant on one allele and a balanced translocation on the other (Bione et al. 2004; Ledig et al. 2015). The p.Arg329Gln variant was found in a heterozygous state in a total of seven of 992 controls from the above studies, and is reported at a frequency of 0.007634 in the admixed American population of the 1000 Genomes Project. Lacombe et al. (2006) found that in vitro binding to non-muscle actin filaments was diminished four-fold in the p.Arg329Gln variant protein compared to the wild type, and Padovano et al. (2011) demonstrated that cells expressing the p.Arg329Gln variant have mislocalized and misassembled tight junctions, were dysmorphic with altered monolayer organization, and showed defects in ciliogenesis and cystogenesis. Based on the evidence, the p.Arg329Gln variant is classified as as a variant of unknown significance but suspicious for pathogenicity for premature ovarian failure 2B. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Uncertain significance (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Premature ovarian failure 2B Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367992.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Uncertain significance.
Uncertain significance (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Premature ovarian failure 2B Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004810151.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Pathogenic (Jul 01, 2006)	no assertion criteria provided Method: literature only	PREMATURE OVARIAN FAILURE 2B (1 family) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031773.5 First in ClinVar: Apr 04, 2013 Last updated: Mar 14, 2021	Publications: PubMed (1) PubMed: 16773570 Comment on evidence: In 5 affected sisters from a consanguineous Lebanese family in which premature ovarian failure mapped to the Xq21.1-q21.33 region (POF2B; 300604), Lacombe et al. (2006) … (more) In 5 affected sisters from a consanguineous Lebanese family in which premature ovarian failure mapped to the Xq21.1-q21.33 region (POF2B; 300604), Lacombe et al. (2006) identified homozygosity for a 1132G-A transition in exon 10 of the POF1B gene that resulted in an arg329-to-gln (R329Q) substitution. The R329Q variant altered the arginine within an amino acid triplet, serine-leucine-arginine, that is part of a protein kinase C (PKC; see 176960) phosphorylation recognition site. Lacombe et al. (2006) demonstrated that the capacity of R329Q mutant POF1B protein to bind nonmuscle actin filaments was diminished 4-fold compared with the wildtype protein, suggesting a function of POF1B in germ cell division. (less)
Likely pathogenic (Feb 09, 2021)	no assertion criteria provided Method: research	Premature ovarian failure 2B Affected status: yes Allele origin: unknown	Reproductive Development, Murdoch Childrens Research Institute Accession: SCV001810164.1 First in ClinVar: Mar 01, 2022 Last updated: Mar 01, 2022

Comment:

Lacombe et al. (2006) identified the POF1B c.986G>A (p.Arg329Gln) variant in a homozygous state in five sisters with POF from a consanguineous Lebanese family. The variant was also identified in a heterozygous state in the unaffected mother and an unaffected sister. The p.Arg329Gln variant has also been reported in two additional patients with POF, including in a heterozygous state in one patient with a second unidentified variant and in one patient with the p.Arg329Gln variant on one allele and a balanced translocation on the other (Bione et al. 2004; Ledig et al. 2015). The p.Arg329Gln variant was found in a heterozygous state in a total of seven of 992 controls from the above studies, and is reported at a frequency of 0.007634 in the admixed American population of the 1000 Genomes Project. Lacombe et al. (2006) found that in vitro binding to non-muscle actin filaments was diminished four-fold in the p.Arg329Gln variant protein compared to the wild type, and Padovano et al. (2011) demonstrated that cells expressing the p.Arg329Gln variant have mislocalized and misassembled tight junctions, were dysmorphic with altered monolayer organization, and showed defects in ciliogenesis and cystogenesis. Based on the evidence, the p.Arg329Gln variant is classified as as a variant of unknown significance but suspicious for pathogenicity for premature ovarian failure 2B. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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
Premature ovarian failure caused by a heterozygous missense mutation in POF1B and a reciprocal translocation 46,X,t(X;3)(q21.1;q21.3).	Ledig S	Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation	2015	PMID: 25676666
The POF1B candidate gene for premature ovarian failure regulates epithelial polarity.	Padovano V	Journal of cell science	2011	PMID: 21940798
Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure.	Lacombe A	American journal of human genetics	2006	PMID: 16773570
Mutation analysis of two candidate genes for premature ovarian failure, DACH2 and POF1B.	Bione S	Human reproduction (Oxford, England)	2004	PMID: 15459172

Text-mined citations for rs75398746 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_024921.4(POF1B):c.986G>A (p.Arg329Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs75398746 ...