NM_001032382.2(PQBP1):c.459_462del (p.Arg153fs) AND Renpenning syndrome

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Nov 11, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000011727.25

Allele description [Variation Report for NM_001032382.2(PQBP1):c.459_462del (p.Arg153fs)]

NM_001032382.2(PQBP1):c.459_462del (p.Arg153fs)

Gene:

PQBP1:polyglutamine binding protein 1 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

Xp11.23

Genomic location:

Preferred name:

NM_001032382.2(PQBP1):c.459_462del (p.Arg153fs)

HGVS:

NC_000023.11:g.48902391AG[4]
NG_015967.1:g.9474AG[4]
NG_015968.2:g.748CT[4]
NG_034300.1:g.14557CT[4]
NM_001032381.2:c.459_462del
NM_001032382.2:c.459_462delMANE SELECT
NM_001032383.2:c.459_462del
NM_001032384.1:c.459_462del
NM_001167989.2:c.459_462del
NM_001167990.2:c.435_438del
NM_001167992.1:c.202-51AG[4]
NM_005710.2:c.459_462del
NM_144495.3:c.293-341AG[4]
NP_001027553.1:p.Arg153fs
NP_001027554.1:p.Arg153fs
NP_001027555.1:p.Arg153fs
NP_001027556.1:p.Arg153fs
NP_001161461.1:p.Arg153fs
NP_001161462.1:p.Arg145fs
NP_005701.1:p.Arg153fs
NC_000023.10:g.48759668AG[4]
NC_000023.10:g.48759668_48759671del
NG_015967.1:g.9482_9485delAGAG
NM_001032381.1:c.459_462delAGAG
NM_001032382.2:c.459_462del
NM_001032383.1:c.459_462delAGAG
NM_005710.2:c.451_454delAGAG
NM_005710.2:c.459_462delAGAG

Note:

NCBI staff reviewed the sequence information reported in PubMed 14634649 Fig. 1 to determine the location of this allele on the current reference sequence.

Protein change:

R145fs

Links:

OMIM: 300463.0002; dbSNP: rs606231193

NCBI 1000 Genomes Browser:

rs606231193

Molecular consequence:

NM_001032381.2:c.459_462del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001032382.2:c.459_462del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001032383.2:c.459_462del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001032384.1:c.459_462del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167989.2:c.459_462del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167990.2:c.435_438del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_005710.2:c.459_462del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167992.1:c.202-51AG[4] - intron variant - [Sequence Ontology: SO:0001627]
NM_144495.3:c.293-341AG[4] - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Name:: Renpenning syndrome
Synonyms:: MENTAL RETARDATION, X-LINKED 55; Renpenning syndrome 1; Mental retardation, X-linked Renpenning type; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010653; MedGen: C0796135; Orphanet: 3242; OMIM: 309500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000031959	OMIM	no assertion criteria provided	Pathogenic (May 1, 2005)	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 9599645, 11950858, 15811016, 15782410, 14634649
SCV000599277	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 14, 2016)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000890116	Génétique des Maladies du Développement, Hospices Civils de Lyon	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 11, 2017)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001451968	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	maternal	research	PubMed (1) [See all records that cite this PMID]
SCV002058467	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:14634649,
SCV002525441	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002558021	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 2, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 14634649, 31840929, 25741868
SCV002583295	Laboratory of Medical Genetics, University of Torino	no assertion criteria provided	Pathogenic (Oct 9, 2022)	maternal	research
SCV003826638	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003842267	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004171597	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	no assertion criteria provided	Pathogenic (Nov 24, 2023)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	research
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
North Indian	maternal	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

A gene for non-specific X-linked mental retardation (MRX55) is located in Xp11.

Deqaqi SC, N'Guessan M, Forner J, Sbiti A, Beldjord C, Chelly J, Sefiani A, Des Portes V.

Ann Genet. 1998;41(1):11-6.

PubMed [citation]

PMID:: 9599645

A new MRXS locus maps to the X chromosome pericentromeric region: a new syndrome or narrow definition of Sutherland-Haan genetic locus?

Fichera M, Borgione E, Avola E, Amata S, Sturnio M, Romano C, Ragusa A.

J Med Genet. 2002 Apr;39(4):276-80. No abstract available.

PubMed [citation]

PMID:: 11950858
PMCID:: PMC1735085

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000031959.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

Description

In affected males of 2 families with X-linked mental retardation (309500), Kalscheuer et al. (2003) identified a deletion of 2 AG dinucleotides at position 3896 of the PQBP1 gene. The mutant protein was predicted to differ by only 2 amino acids from the normal protein. Affected individuals from 1 family, which had been reported as MRX55 (see 309500) by Deqaqi et al. (1998), were moderately retarded but had no other clinical signs, except for a somewhat smaller body size in 1 individual. In contrast, all affected members of the second family, which had not been reported previously, had microcephaly in addition to mental retardation. One member also had anal atresia, and another had complete situs inversus. Kalscheuer et al. (2003) suggested that this clinical variability might be due to differences in the genetic background; the mildly affected family was from Morocco, while the other family was from the Netherlands. The disorder was not progressive in any of these families.

In affected members and obligate carriers of a family with MRXS3, previously described by Fichera et al. (2002), Fichera et al. (2005) identified the 3896delAGAG mutation in the PQBP1 gene. The authors observed skewed X inactivation in 8 of 9 heterozygous females in this family; the inactivated X chromosome was of maternal origin.

In a family (K8600) with Renpenning syndrome, Stevenson et al. (2005) identified a 4-bp deletion in exon 4 of the PQBP1 gene, which they stated was identical to that previously identified by Kalscheuer et al. (2003) in the MRX55 family, although Stevenson et al. (2005) denoted the mutation as 459-462delAGAG. The deletion causes a frameshift and a premature stop codon, resulting in a protein that partially lacks the PRD domain and completely lacks the NLS and C2 domains. The deletion was found in all affected males and obligate carriers.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV000599277.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Génétique des Maladies du Développement, Hospices Civils de Lyon, SCV000890116.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, SCV001451968.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	North Indian	1	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From 3billion, SCV002058467.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002525441.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002558021.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive disease. There is one report of an affected female carrier (PMID: 31840929). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 4 of 6). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals. This variant has been reported as a recurring, common pathogenic variant (PMID: 31840929, 14634649). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, University of Torino, SCV002583295.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003826638.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lifecell International Pvt. Ltd, SCV003842267.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV004171597.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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