GeneBe

rs606231193

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001032382.2(PQBP1):​c.459_462delAGAG​(p.Arg153SerfsTer41) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000913 in 1,095,312 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 21)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

PQBP1
NM_001032382.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23

Conservation

PhyloP100: 4.18
Variant links:
Genes affected
PQBP1 (HGNC:9330): (polyglutamine binding protein 1) This gene encodes a nuclear polyglutamine-binding protein that is involved with transcription activation. The encoded protein contains a WW domain. Mutations in this gene have been found in patients with Renpenning syndrome 1 and other syndromes with X-linked cognitive disability. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene.[provided by RefSeq, Nov 2009]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-48902390-CAGAG-C is Pathogenic according to our data. Variant chrX-48902390-CAGAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48902390-CAGAG-C is described in Lovd as [Pathogenic]. Variant chrX-48902390-CAGAG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PQBP1NM_001032382.2 linkc.459_462delAGAG p.Arg153SerfsTer41 frameshift_variant Exon 5 of 7 ENST00000447146.7 NP_001027554.1 O60828-1A0A0S2Z4V5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PQBP1ENST00000447146.7 linkc.459_462delAGAG p.Arg153SerfsTer41 frameshift_variant Exon 5 of 7 1 NM_001032382.2 ENSP00000391759.2 O60828-1

Frequencies

GnomAD3 genomes
Cov.:
21
GnomAD4 exome
AF:
9.13e-7
AC:
1
AN:
1095312
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
360984
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
21
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:23
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Renpenning syndrome Pathogenic:14
Jan 03, 2022
3billion
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000010980, PMID:14634649). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PVS1,PM3(strong),PS3,PM2 -

Jul 11, 2017
Génétique des Maladies du Développement, Hospices Civils de Lyon
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 08, 2022
Institute of Immunology and Genetics Kaiserslautern
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG Criteria: PVS1, PS3, PM2, PP1, PP5; Variant was found in hemizygous state. -

Oct 09, 2022
Laboratory of Medical Genetics, University of Torino
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

May 01, 2005
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Nov 11, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 24, 2023
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 14, 2016
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Oct 09, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Renpenning syndrome (MIM#309500). (I) 0109 - This gene is associated with X-linked recessive disease. However, there is a report of an affected female carrier (PMID: 31840929). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a recurring, common pathogenic variant (ClinVar, PMIDs: 31840929, 14634649). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

-
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

-
Lifecell International Pvt. Ltd
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

A Hemizygote Frameshift variant c.451_454delAGAG in Exon 4 of the PQBP1 gene that results in the amino acid substitution p.Arg153fs*41 was identified. The observed variant has a minor allele frequency of 0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic (Variant ID:10980). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PVS1+PS4_Supporting+PM6_Supporting -

not provided Pathogenic:5
May 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg153Serfs*41) in the PQBP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PQBP1 are known to be pathogenic (PMID: 20950397). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Renpenning syndrome (PMID: 20950397, 30500859, 31316545). ClinVar contains an entry for this variant (Variation ID: 10980). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Apr 01, 2018
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 18, 2024
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 25, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Additional published functional studies demonstrate a damaging effect causing loss of the YxxPxxVL motif that is essential for binding with the spliceosomal protein U5-15kD (Mizuguchi et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as the variant transcripts were markedly reduced compared to controls, indicating nonsense mediated mRNA decay (Kalscheuer et al. 2003); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19847789, 28795356, 30315573, 20886605, 24781215, 14634649, 26046437, 26350204, 28073926, 25533962, 28152038, 29286531, 30500859, 20950397, 30842647, 30951824, 31316545, 31840929, 31840915, 33258288, 27535533) -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1
Jun 06, 2014
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hyperactivity;C0454644:Delayed speech and language development;C4551563:Microcephaly Pathogenic:1
May 16, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

See cases Pathogenic:1
Apr 26, 2021
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1_very strong;PP5_strong;PM2_supporting -

Intellectual disability Pathogenic:1
Feb 13, 2019
Raymond Lab, University of Cambridge
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs606231193; hg19: chrX-48759667; API