VCV000444045.8 - ClinVar

NM_001387263.1(PATL2):c.478C>T (p.Arg160Ter)

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.

(4)

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.

Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001387263.1(PATL2):c.478C>T (p.Arg160Ter)

Variation ID: 444045 Accession: VCV000444045.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q21.1 15: 44672425 (GRCh38) [ NCBI UCSC ] 15: 44964623 (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	Dec 26, 2017	Apr 15, 2023	Apr 2, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001387263.1:c.478C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001374192.1:p.Arg160Ter	nonsense
NM_001145112.2:c.478C>T	NP_001138584.1:p.Arg160Ter	nonsense
NM_001330283.2:c.-173C>T		5 prime UTR
NM_001387260.1:c.478C>T	NP_001374189.1:p.Arg160Ter	nonsense
NM_001387261.1:c.478C>T	NP_001374190.1:p.Arg160Ter	nonsense
NM_001387262.1:c.478C>T	NP_001374191.1:p.Arg160Ter	nonsense
NM_001387264.1:c.478C>T	NP_001374193.1:p.Arg160Ter	nonsense
NC_000015.10:g.44672425G>A
NC_000015.9:g.44964623G>A

... more HGVS ... less HGVS

Protein change

R160*

Other names

NM_001145112.1:c.478C>T(p.Arg160Ter)

Canonical SPDI

NC_000015.10:44672424:G:A

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

loss_of_function_variant; Sequence Ontology [ SO:0002054]

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00004

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA270095947 OMIM: 614661.0001 dbSNP: rs548527219 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.
LOC130056977	-	-	-	GRCh38	-	4
PATL2		-	-	GRCh38 GRCh38 GRCh37	59	80

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.
Oocyte maturation defect 4	Likely pathogenic (3)	criteria provided, single submitter	Apr 16, 2018	RCV000512633.6
Oocyte maturation defect 2	Likely pathogenic (1)	criteria provided, single submitter	Apr 2, 2021	RCV001449808.4

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.
Likely pathogenic (Apr 16, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Oocyte maturation defect 4 Affected status: unknown Allele origin: germline	SIB Swiss Institute of Bioinformatics Accession: SCV000787499.1 First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018	Publications: PubMed (1) PubMed: 28965844 Comment: This variant is interpreted as a Likely Pathogenic, for Oocyte maturation defect 4, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent … (more) This variant is interpreted as a Likely Pathogenic, for Oocyte maturation defect 4, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:28965844). PVS1-Strong => PVS1 downgraded in strength to Strong (PMID:28965844). (less)
Likely pathogenic (Apr 02, 2021)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Oocyte maturation defect 2 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV001653100.1 First in ClinVar: May 29, 2021 Last updated: May 29, 2021	Publications: PubMed (3) PubMed: 32552793‚ 28965844‚ 29661911 Comment: The p.Arg160X variant in PATL2 has been reported as homozygous in 8 Middle Eastern and North African women with oocyte maturation arrest and segregated with … (more) The p.Arg160X variant in PATL2 has been reported as homozygous in 8 Middle Eastern and North African women with oocyte maturation arrest and segregated with disease in 1 affected individual from 1 family (Maddirevula 2017 PMID: 28965844, Christou-Kent 2018 PMID: 29661911, Okutman 2021 PMCID: PMC7999157). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 444045) and has also been identified in 0.003% (3/154084) of pan-ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 160, which is predicted to lead to a truncated or absent protein. Loss of function of the PATL2 gene is strongly associated to autosomal recessive oocyte maturation arrest. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive oocyte maturation arrest. ACMG/AMP Criteria applied: PVS1_Strong, PM3, PM2_Supporting. (less) Number of individuals with the variant: 1
Pathogenic (Feb 09, 2021)	no assertion criteria provided Method: clinical testing	Oocyte maturation defect 4 (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV001478471.1 First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021	Publications: PubMed (1) PubMed: 28965844 Comment: Patient is from a consanguineous family. She underwent four failed IVF attempts; all retrieved oocytes were either degenerate or immature. Clinical Features: Female infertility (present) Sex: female Geographic origin: Turkey
Pathogenic (Apr 10, 2023)	no assertion criteria provided Method: literature only	OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000608332.3 First in ClinVar: Oct 30, 2017 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 28965844 Comment on evidence: In 2 sisters from a consanguineous Saudi family (family A) with primary infertility due to oocyte maturation arrest (OZEMA4; 617743), Maddirevula et al. (2017) identified … (more) In 2 sisters from a consanguineous Saudi family (family A) with primary infertility due to oocyte maturation arrest (OZEMA4; 617743), Maddirevula et al. (2017) identified homozygosity for a c.478C-T transition (c.478C-T, NM_001145112.1) in exon 6 of the PATL2 gene, resulting in an arg160-to-ter (R160X) substitution causing premature termination with complete loss of the RNA-binding domain. The mutation segregated with female infertility in the family: the father and 2 brothers who were also homozygous for the mutation were fertile. The R160X variant was not found in 2,379 Saudi exomes, and was very rare in the ExAC database (minor allele frequency, 0.00003362). (less)

Comment:

This variant is interpreted as a Likely Pathogenic, for Oocyte maturation defect 4, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:28965844). PVS1-Strong => PVS1 downgraded in strength to Strong (PMID:28965844).

Comment:

The p.Arg160X variant in PATL2 has been reported as homozygous in 8 Middle Eastern and North African women with oocyte maturation arrest and segregated with disease in 1 affected individual from 1 family (Maddirevula 2017 PMID: 28965844, Christou-Kent 2018 PMID: 29661911, Okutman 2021 PMCID: PMC7999157). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 444045) and has also been identified in 0.003% (3/154084) of pan-ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 160, which is predicted to lead to a truncated or absent protein. Loss of function of the PATL2 gene is strongly associated to autosomal recessive oocyte maturation arrest. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive oocyte maturation arrest. ACMG/AMP Criteria applied: PVS1_Strong, PM3, PM2_Supporting.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)			Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV001478471.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics.	Maddirevula S	Genome biology	2020	PMID: 32552793
PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice.	Christou-Kent M	EMBO molecular medicine	2018	PMID: 29661911
Female Infertility Caused by Mutations in the Oocyte-Specific Translational Repressor PATL2.	Maddirevula S	American journal of human genetics	2017	PMID: 28965844

Text-mined citations for rs548527219 ...

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 Oct 15, 2023

ClinVar Genomic variation as it relates to human health

NM_001387263.1(PATL2):c.478C>T (p.Arg160Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs548527219 ...