VCV000010982.31 - ClinVar

NM_001032382.2(PQBP1):c.640dup (p.Arg214fs)

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.

(5)

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.

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_001032382.2(PQBP1):c.640dup (p.Arg214fs)

Variation ID: 10982 Accession: VCV000010982.31

Type and length

Duplication, 1 bp

Location

Cytogenetic: Xp11.23 X: 48902788-48902789 (GRCh38) [ NCBI UCSC ] X: 48760065-48760066 (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	Apr 4, 2013	Oct 20, 2024	Aug 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001032382.2:c.640dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001027554.1:p.Arg214fs	frameshift
NM_001032381.2:c.640dup	NP_001027553.1:p.Arg214fs	frameshift
NM_001032383.2:c.640dup	NP_001027555.1:p.Arg214fs	frameshift
NM_001032384.1:c.640dup	NP_001027556.1:p.Arg214fs	frameshift
NM_001167989.2:c.637dup	NP_001161461.1:p.Arg213fs	frameshift
NM_001167990.2:c.616dup	NP_001161462.1:p.Arg206fs	frameshift
NM_001167992.1:c.340dup	NP_001161464.1:p.Arg114fs	frameshift
NM_005710.2:c.640dup	NP_005701.1:p.Arg214fs	frameshift
NM_005710.2:c.640dupC
NM_144495.3:c.355dup	NP_652766.1:p.Arg119fs	frameshift
NC_000023.11:g.48902794dup
NC_000023.10:g.48760071dup
NG_015967.1:g.9877dup
NG_015968.2:g.361dup
NG_034300.1:g.14170dup

... more HGVS ... less HGVS

Protein change

R114fs, R119fs, R206fs, R214fs, R213fs

Other names

Canonical SPDI

NC_000023.11:48902788:CCCCCC:CCCCCCC

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

ClinGen: CA250048 OMIM: 300463.0004 dbSNP: rs606231196 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 15024694 Fig. 1A to determine the location of this allele on the current reference sequence.

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.
PQBP1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	144	332

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.
Renpenning syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 5, 2013	RCV000011729.14
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 29, 2024	RCV000599325.25

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.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Renpenning syndrome Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002525442.1 First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022
Pathogenic (Aug 29, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000709914.2 First in ClinVar: Apr 02, 2018 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate a damaging effect: loss of the YxxPxxVL motif that is essential for binding with the spliceosomal protein U5-15kD (PMID: 24781215); Frameshift … (more) Published functional studies demonstrate a damaging effect: loss of the YxxPxxVL motif that is essential for binding with the spliceosomal protein U5-15kD (PMID: 24781215); Frameshift variant predicted to result in protein truncation, as the last 52 amino acids are replaced with 12 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.641insC; This variant is associated with the following publications: (PMID: 9545405, 26633545, 24781215, 27535533, 15024694, 24077912) (less)
Pathogenic (Feb 05, 2013)	criteria provided, single submitter (Yang et al. 2013) Method: clinical testing	Renpenning syndrome 1 (X-linked inheritance) Affected status: yes Allele origin: maternal	Baylor Genetics Study: Adult_WES Accession: SCV000245528.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Publications: PubMed (3) PubMed: 26633545‚ 15024694‚ 9545405 Comment: This variant has been previously reported as disease-causing and was found once in our laboratory maternally inherited in a 40-year-old male with intellectual disability, autism, … (more) This variant has been previously reported as disease-causing and was found once in our laboratory maternally inherited in a 40-year-old male with intellectual disability, autism, dysmorphic features, strabismus (less) Number of individuals with the variant: 1 Age: 40-49 years Sex: male Ethnicity/Population group: Causasians
Pathogenic (Jun 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001501106.23 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 3
Pathogenic (Apr 01, 2004)	no assertion criteria provided Method: literature only	RENPENNING SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031961.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (3) PubMed: 13981686‚ 9545405‚ 15024694 Comment on evidence: Renpenning et al. (1962) described a Canadian Mennonite family in which 20 males in 3 generations had mental retardation (309500). Manifestations in affected males included … (more) Renpenning et al. (1962) described a Canadian Mennonite family in which 20 males in 3 generations had mental retardation (309500). Manifestations in affected males included microcephaly, short stature, and small testes; carrier females appeared normal. Stevenson et al. (1998) mapped the disorder in this family to Xp11.4-p11.2. In affected members of this family, Lenski et al. (2004) identified a 1-bp insertion in the PQBP1 gene, 641insC, resulting in a frameshift with a premature stop codon. (less)

Comment:

Published functional studies demonstrate a damaging effect: loss of the YxxPxxVL motif that is essential for binding with the spliceosomal protein U5-15kD (PMID: 24781215); Frameshift variant predicted to result in protein truncation, as the last 52 amino acids are replaced with 12 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.641insC; This variant is associated with the following publications: (PMID: 9545405, 26633545, 24781215, 27535533, 15024694, 24077912)

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
Molecular diagnostic experience of whole-exome sequencing in adult patients.	Posey JE	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26633545
Novel truncating mutations in the polyglutamine tract binding protein 1 gene (PQBP1) cause Renpenning syndrome and X-linked mental retardation in another family with microcephaly.	Lenski C	American journal of human genetics	2004	PMID: 15024694
Renpenning syndrome maps to Xp11.	Stevenson RE	American journal of human genetics	1998	PMID: 9545405
Familial sex-linked mental retardation.	RENPENNING H	Canadian Medical Association journal	1962	PMID: 13981686

Text-mined citations for rs606231196 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001032382.2(PQBP1):c.640dup (p.Arg214fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs606231196 ...