rs1557041672

Positions:

• chrX-48902740-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001032382.2(PQBP1):​c.586C>T​(p.Arg196*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PQBP1 NM_001032382.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.15

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]

PQBP1 (HGNC:):

ACMG classification

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-48902740-C-T is Pathogenic according to our data. Variant chrX-48902740-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48902740-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PQBP1	NM_001032382.2	c.586C>T	p.Arg196*	stop_gained	6/7	ENST00000447146.7	NP_001027554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PQBP1	ENST00000447146.7	c.586C>T	p.Arg196*	stop_gained	6/7	1	NM_001032382.2	ENSP00000391759.2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1090252 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 357692

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renpenning syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 15, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,. This variant was detected in hemizygous state. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The hemizygous p.Arg196Ter variant in PQBP1 was identified by our study in two brothers with Renpenning syndrome. The p.Arg196Ter variant in PQBP1 has been previously reported in 3 unrelated individuals with Renpenning syndrome 1 (PMID: 30244542, PMID: 20950397, ClinVar SCV000807517.2) and segregated with disease in 3 affected relatives from one family (PMID: 30244542). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 545093) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 196. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the PQBP1 gene is an established disease mechanism in Renpenning syndrome 1. In summary, additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for X-linked Renpenning syndrome 1. ACMG/AMP Criteria applied: PVS1_Strong, PS4_Moderate, PM2_Supporting, PP1 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This variant has been previously reported as disease-causing and was found once in our laboratory maternally inherited in a 9-month-old male with developmental delay, dysmorphisms, microcephaly, failure to thrive, genital anomalies -
Pathogenic, criteria provided, single submitter	research	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Oct 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2022	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 70 amino acids are lost, 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); This variant is associated with the following publications: (PMID: 25525159, 21315190, 20950397, 30244542, 25326635, 33504798) -

PQBP1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

The PQBP1 c.586C>T variant is predicted to result in premature protein termination (p.Arg196*). This variant has been reported in individuals with clinically recognizable characteristics of Renpenning syndrome (patient LIII-5, Germanaud et al. 2011. PubMed ID: 20950397; family 1, Abdel-Salam et al. 2018. PubMed ID: 30244542). This variant was also reported de novo in an individual from an X-linked developmental disorder study (Table S2: individual 272, Martin et al. 2021. PubMed ID: 33504798). This variant has not been reported in a large population database, indicating this variant is rare. This variant is reported as having interpretations of pathogenic and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/545093/). Nonsense variants in PQBP1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.76
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs1557041672; hg19: chrX-48760017;