VCV000010979.8 - ClinVar

NM_001032382.2(PQBP1):c.461_462dup (p.Arg155fs)

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.

(6)

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.461_462dup (p.Arg155fs)

Variation ID: 10979 Accession: VCV000010979.8

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: Xp11.23 X: 48902390-48902391 (GRCh38) [ NCBI UCSC ] X: 48759667-48759668 (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 8, 2024	Aug 1, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_001032382.2:c.461_462dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001027554.1:p.Arg155fs	frameshift
NM_001032381.2:c.461_462dup	NP_001027553.1:p.Arg155fs	frameshift
NM_001032382.1:c.461_462dup
NM_001032383.1:c.461_462dup		frameshift
NM_001032383.2:c.461_462dup	NP_001027555.1:p.Arg155fs	frameshift
NM_001032384.1:c.461_462dup	NP_001027556.1:p.Arg155fs	frameshift
NM_001167989.2:c.461_462dup	NP_001161461.1:p.Arg155fs	frameshift
NM_001167990.2:c.437_438dup	NP_001161462.1:p.Arg147fs	frameshift
NM_001167992.1:c.202-51AG[7]		intron variant
NM_005710.2:c.461_462dup	NP_005701.1:p.Arg155fs	frameshift
NM_005710.2:c.461_462dupAG
NM_144495.3:c.293-341AG[7]		intron variant
NC_000023.11:g.48902391AG[7]
NC_000023.10:g.48759668AG[7]
NG_015967.1:g.9474AG[7]
NG_015968.2:g.748CT[7]
NG_034300.1:g.14557CT[7]

... more HGVS ... less HGVS

Protein change

R147fs, R155fs

Other names

Canonical SPDI

NC_000023.11:48902390:AGAGAGAGAGAG:AGAGAGAGAGAGAG

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: CA121282 OMIM: 300463.0001 dbSNP: rs606231193 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 14634649 Fig. 1 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 (4)	criteria provided, multiple submitters, no conflicts	-	RCV000011726.12
not provided	Pathogenic (1)	criteria provided, single submitter	Aug 1, 2018	RCV001008093.1
PQBP1-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 11, 2024	RCV004745153.1

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.
Pathogenic (Aug 01, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001167838.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Comment: The c.461_462dupAG variant, denoted as 3898_3899dupAG due to alternative nomenclature, in the PQBP1 gene has been reported previously to segregate in affected males from two … (more) The c.461_462dupAG variant, denoted as 3898_3899dupAG due to alternative nomenclature, in the PQBP1 gene has been reported previously to segregate in affected males from two families with X-linked mental retardation, including one family with Sutherland-Haan syndrome (Kalscheuer et al., 2003). Functional studies of the variant, denoted as 3898_3899dupAG due to alternative nomenclature, demonstrate the abnormal PQBP1 protein is not properly localized in the nucleus (Kalscheuer et al., 2003). In addition, functional studies of the variant, denoted as c.463_464dupAG due to alternative nomenclature, demonstrate the abnormal PQBP1 protein affects fragile X mental retardation protein (FMRP) degradation leading to FMRP-dependent synaptic defects (Zhang et al., 2017). The c.461_462dupAG variant causes a frameshift starting with codon Arginine 155, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 41 of the new reading frame, denoted p.Arg155SerfsX41. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.461_462dupAG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.461_462dupAG as a pathogenic variant. (less)
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: SCV002525446.1 First in ClinVar: Jun 10, 2022 Last updated: Jun 10, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renpenning syndrome Affected status: yes Allele origin: de novo	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV002559194.1 First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renpenning syndrome Affected status: yes Allele origin: maternal	Molecular Genetics Lab, CHRU Brest Accession: SCV004697775.1 First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024
Pathogenic (Dec 01, 2003)	no assertion criteria provided Method: literature only	RENPENNING SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031958.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 3177467‚ 14634649 Comment on evidence: In all affected males from a family (family SHS) with an X-linked mental retardation syndrome (309500), previously reported by Sutherland et al. (1988), Kalscheuer et … (more) In all affected males from a family (family SHS) with an X-linked mental retardation syndrome (309500), previously reported by Sutherland et al. (1988), Kalscheuer et al. (2003) identified an insertion of an extra AG dinucleotide at position 3900 of the PQBP1 gene. Affected males showed mental retardation, short stature, microcephaly, brachycephaly, spastic diplegia, small testes, and anal stenosis or atresia. (Sutherland et al. (1988) had called this disorder MRX2.) Kalscheuer et al. (2003) identified the same AG duplication in a second family with X-linked mental retardation (see 309500), but the affected males showed no spastic diplegia or small testes. In both families the disease was not progressive. (less)
Pathogenic (Sep 11, 2024)	no assertion criteria provided Method: clinical testing	PQBP1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005355139.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PQBP1 c.461_462dupAG variant is predicted to result in a frameshift and premature protein termination (p.Arg155Serfs41). This variant has been reported to segregate with disease … (more) The PQBP1 c.461_462dupAG variant is predicted to result in a frameshift and premature protein termination (p.Arg155Serfs41). This variant has been reported to segregate with disease in two families with X-linked intellectual disability (families with AG duplication in Kalscheuer et al. 2003. PubMed ID: 14634649). In vitro experimental studies indicate this variant impacts protein function (reported as c.463_464dupAG in Mizuguchi et al. 2014. PubMed ID: 24781215 and Zhang et al. 2017. PubMed ID: 28073926). This variant is reported in 0.0014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in PQBP1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

Comment:

The c.461_462dupAG variant, denoted as 3898_3899dupAG due to alternative nomenclature, in the PQBP1 gene has been reported previously to segregate in affected males from two families with X-linked mental retardation, including one family with Sutherland-Haan syndrome (Kalscheuer et al., 2003). Functional studies of the variant, denoted as 3898_3899dupAG due to alternative nomenclature, demonstrate the abnormal PQBP1 protein is not properly localized in the nucleus (Kalscheuer et al., 2003). In addition, functional studies of the variant, denoted as c.463_464dupAG due to alternative nomenclature, demonstrate the abnormal PQBP1 protein affects fragile X mental retardation protein (FMRP) degradation leading to FMRP-dependent synaptic defects (Zhang et al., 2017). The c.461_462dupAG variant causes a frameshift starting with codon Arginine 155, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 41 of the new reading frame, denoted p.Arg155SerfsX41. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.461_462dupAG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.461_462dupAG as a pathogenic variant.

Comment:

The PQBP1 c.461_462dupAG variant is predicted to result in a frameshift and premature protein termination (p.Arg155Serfs*41). This variant has been reported to segregate with disease in two families with X-linked intellectual disability (families with AG duplication in Kalscheuer et al. 2003. PubMed ID: 14634649). In vitro experimental studies indicate this variant impacts protein function (reported as c.463_464dupAG in Mizuguchi et al. 2014. PubMed ID: 24781215 and Zhang et al. 2017. PubMed ID: 28073926). This variant is reported in 0.0014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in PQBP1 are expected to be pathogenic. This variant is interpreted as pathogenic.

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
Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation.	Kalscheuer VM	Nature genetics	2003	PMID: 14634649
Linkage studies with the gene for an X-linked syndrome of mental retardation, microcephaly and spastic diplegia (MRX2).	Sutherland GR	American journal of medical genetics	1988	PMID: 3177467

Text-mined citations for rs606231193 ...

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 13, 2024

ClinVar Genomic variation as it relates to human health

NM_001032382.2(PQBP1):c.461_462dup (p.Arg155fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs606231193 ...