VCV000010980.62 - ClinVar

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

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.

(23)

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/Likely 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.459_462del (p.Arg153fs)

Variation ID: 10980 Accession: VCV000010980.62

Type and length

Microsatellite, 4 bp

Location

Cytogenetic: Xp11.23 X: 48902391-48902394 (GRCh38) [ NCBI UCSC ] X: 48759668-48759671 (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	Dec 7, 2024	Oct 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001032382.2:c.459_462del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001027554.1:p.Arg153fs	frameshift
NM_001032381.1:c.459_462delAGAG
NM_001032381.2:c.459_462del	NP_001027553.1:p.Arg153fs	frameshift
NM_001032382.1:c.459_462delAGAG
NM_001032383.1:c.459_462delAGAG
NM_001032383.2:c.459_462del	NP_001027555.1:p.Arg153fs	frameshift
NM_001032384.1:c.459_462del	NP_001027556.1:p.Arg153fs	frameshift
NM_001167989.2:c.459_462del	NP_001161461.1:p.Arg153fs	frameshift
NM_001167990.2:c.435_438del	NP_001161462.1:p.Arg145fs	frameshift
NM_001167992.1:c.202-51AG[4]		intron variant
NM_005710.2:c.451_454delAGAG
NM_005710.2:c.459_462del	NP_005701.1:p.Arg153fs	frameshift
NM_005710.2:c.459_462delAGAG
NM_144495.3:c.293-341AG[4]		intron variant
NC_000023.11:g.48902391AG[4]
NC_000023.10:g.48759668AG[4]
NG_015967.1:g.9474AG[4]
NG_015968.2:g.748CT[4]
NG_034300.1:g.14557CT[4]

... more HGVS ... less HGVS

Protein change

R145fs, R153fs

Other names

Canonical SPDI

NC_000023.11:48902390:AGAGAGAGAGAG:AGAGAGAG

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: CA121283 OMIM: 300463.0002 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 (14)	criteria provided, multiple submitters, no conflicts	Oct 9, 2024	RCV000011727.31
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 18, 2024	RCV000254782.35
Delayed speech and language development Hyperactivity Microcephaly	Pathogenic (1)	no assertion criteria provided	May 16, 2016	RCV000414864.6
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jun 6, 2014	RCV000623728.6
Intellectual disability	Likely pathogenic (1)	criteria provided, single submitter	Feb 13, 2019	RCV000850214.6
See cases	Pathogenic (1)	criteria provided, single submitter	Apr 26, 2021	RCV001420268.6

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 (Jun 14, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renpenning syndrome Affected status: yes Allele origin: de novo	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals Accession: SCV000599277.1 First in ClinVar: Sep 17, 2016 Last updated: Sep 17, 2016
Pathogenic (Jul 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renpenning syndrome Affected status: yes Allele origin: maternal	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005382115.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: ACMG Criteria: PVS1, PS3, PM2, PP1, PP5; Variant was found in hemizygous state. Clinical Features: Double outlet right ventricle (present)
Pathogenic (Oct 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renpenning syndrome (X-linked recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002558021.3 First in ClinVar: Aug 08, 2022 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 14634649‚ 31840929 Comment: 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 … (more) 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 (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renpenning syndrome Affected status: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005416370.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PM2_Supporting+PVS1+PS4_Supporting+PM6_Supporting
Pathogenic (Oct 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Renpenning syndrome Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV005420675.1 First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024	Comment: PVS1,PM3(strong),PS3,PM2
Pathogenic (Jul 11, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renpenning syndrome (X-linked inheritance) Affected status: yes Allele origin: de novo	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV000890116.1 First in ClinVar: Sep 17, 2016 Last updated: Sep 17, 2016
Likely pathogenic (Feb 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual disability Affected status: yes Allele origin: unknown	Raymond Lab, University of Cambridge Accession: SCV000897752.1 First in ClinVar: Sep 14, 2019 Last updated: Sep 14, 2019	Number of individuals with the variant: 2 Family history: yes
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (X-linked recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447678.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Microcephaly (present) , Global developmental delay (present) Sex: male
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Renpenning syndrome (X-linked recessive inheritance) Affected status: yes Allele origin: maternal	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences Accession: SCV001451968.1 First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021	Clinical Features: Microcephaly (present) , Generalized lipodystrophy (present) , Global developmental delay (present) , Scapular winging (present) , Thoracic scoliosis (present) , Muscular atrophy (present) , Long … (more) Microcephaly (present) , Generalized lipodystrophy (present) , Global developmental delay (present) , Scapular winging (present) , Thoracic scoliosis (present) , Muscular atrophy (present) , Long face (present) , Deeply set eye (present) , Hypertelorism (present) , Malar flattening (present) , Sandal gap (present) (less) Zygosity: Hemizygote Age: 20-29 years Sex: male Ethnicity/Population group: North Indian Geographic origin: India
Pathogenic (Apr 26, 2021)	criteria provided, single submitter (Parc Tauli Hospital Assertion Criteria 2021) Method: clinical testing	See cases (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli Accession: SCV001622688.1 First in ClinVar: May 23, 2021 Last updated: May 23, 2021	Comment: PVS1_very strong;PP5_strong;PM2_supporting Clinical Features: Growth delay (present) , Microcephaly (present) , Abnormal facial shape (present) , Global developmental delay (present) , Attention deficit hyperactivity disorder (present) , Autistic behavior … (more) Growth delay (present) , Microcephaly (present) , Abnormal facial shape (present) , Global developmental delay (present) , Attention deficit hyperactivity disorder (present) , Autistic behavior (present) , Sleep abnormality (present) , Strabismus (present) (less) Zygosity: Hemizygote Sex: male
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renpenning syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002058467.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:14634649 PMID:14634649 Comment: 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 … (more) 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. (less) Clinical Features: Attention deficit hyperactivity disorder (present) , Imperforate anus (present) , Intellectual disability, mild (present) , Long face (present) , Microcephaly (present) , Periorbital fullness (present) … (more) Attention deficit hyperactivity disorder (present) , Imperforate anus (present) , Intellectual disability, mild (present) , Long face (present) , Microcephaly (present) , Periorbital fullness (present) , Pulmonary artery stenosis (present) , Thick vermilion border (present) , Wide mouth (present) (less) Zygosity: Hemizygote
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: SCV002525441.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022
Pathogenic (Jun 06, 2014)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741124.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (3) PubMed: 14634649‚ 20950397‚ 20886605 Observation 1: Number of individuals with the variant: 1 Clinical Features: Neurodevelopmental delay (present) , Congenital microcephaly (present) , Gastroesophageal reflux (present) , Failure to thrive (present) , Muscular hypotonia (present) , Respiratory tract infection (present) … (more) Neurodevelopmental delay (present) , Congenital microcephaly (present) , Gastroesophageal reflux (present) , Failure to thrive (present) , Muscular hypotonia (present) , Respiratory tract infection (present) , Dysphagia (present) , Abnormality of the upper respiratory tract (present) , Chronic otitis media (present) , Large beaked nose (present) , Broad columella (present) , Abnormality of the philtrum (present) , Pointed chin (present) , Abnormality of the palmar creases (present) , Overlapping toe (present) (less) Sex: male Ethnicity/Population group: Caucasian Observation 2: Number of individuals with the variant: 1 Clinical Features: Microcephaly (present) , Hyperactivity (present) , Short stature (present) , Autistic disorder of childhood onset (present) , Joint laxity (present) , Insomnia (present) , Anxiety … (more) Microcephaly (present) , Hyperactivity (present) , Short stature (present) , Autistic disorder of childhood onset (present) , Joint laxity (present) , Insomnia (present) , Anxiety (present) , Ptosis (present) , Micrognathia (present) , Low-set ears (present) , Abnormality of the pinna (present) , Midface retrusion (present) , Asymmetry of the thorax (present) , Scoliosis (present) , Pectus carinatum (present) , Long fingers (present) , Long toe (present) , Abnormality of the palmar creases (present) , Limited interphalangeal movement (present) , Cafe-au-lait spot (present) , Heart murmur (present) , Encephalopathy (present) (less) Sex: male Ethnicity/Population group: Hispanic
Pathogenic (Mar 25, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322220.9 First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renpenning syndrome (X-linked recessive inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003842267.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: A Hemizygote Frameshift variant c.451_454delAGAG in Exon 4 of the PQBP1 gene that results in the amino acid substitution p.Arg153fs41 was identified. The observed variant … (more) A Hemizygote Frameshift variant c.451_454delAGAG in Exon 4 of the PQBP1 gene that results in the amino acid substitution p.Arg153fs41 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. (less) Zygosity: Hemizygote Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (Nov 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renpenning syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003826638.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 22, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003444656.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 20950397‚ 30500859‚ 31316545 Comment: This sequence change creates a premature translational stop signal (p.Arg153Serfs41) in the PQBP1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg153Serfs41) 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. (less)
Pathogenic (Mar 18, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198413.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Apr 01, 2018)	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: SCV001246842.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 4
Pathogenic (May 01, 2005)	no assertion criteria provided Method: literature only	RENPENNING SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031959.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (5) PubMed: 14634649‚ 9599645‚ 11950858‚ 15811016‚ 15782410 Comment on evidence: 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 … (more) 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. (less)
Pathogenic (May 16, 2016)	no assertion criteria provided Method: clinical testing	Microcephaly Delayed speech and language development Hyperactivity Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492595.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Oct 09, 2022)	no assertion criteria provided Method: research	Renpenning syndrome Affected status: yes Allele origin: maternal	Laboratory of Medical Genetics, University of Torino Accession: SCV002583295.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022	Sex: male
Pathogenic (Nov 24, 2023)	no assertion criteria provided Method: clinical testing	Renpenning syndrome Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004171597.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023
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Comment:

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

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

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
Renpenning syndrome in a female.	Cho RY	American journal of medical genetics. Part A	2020	PMID: 31840929
Rare Genetic Variation in 135 Families With Family History Suggestive of X-Linked Intellectual Disability.	Sanchis-Juan A	Frontiers in genetics	2019	PMID: 31316545
Identification of candidate gene FAM183A and novel pathogenic variants in known genes: High genetic heterogeneity for autosomal recessive intellectual disability.	McSherry M	PloS one	2018	PMID: 30500859
The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males.	Germanaud D	Clinical genetics	2011	PMID: 20950397
Mutation in PQBP1 is associated with periventricular heterotopia.	Sheen VL	American journal of medical genetics. Part A	2010	PMID: 20886605
Skewed X-inactivation in a family with mental retardation and PQBP1 gene mutation.	Fichera M	Clinical genetics	2005	PMID: 15811016
Renpenning syndrome comes into focus.	Stevenson RE	American journal of medical genetics. Part A	2005	PMID: 15782410
Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation.	Kalscheuer VM	Nature genetics	2003	PMID: 14634649
A new MRXS locus maps to the X chromosome pericentromeric region: a new syndrome or narrow definition of Sutherland-Haan genetic locus?	Fichera M	Journal of medical genetics	2002	PMID: 11950858
A gene for non-specific X-linked mental retardation (MRX55) is located in Xp11.	Deqaqi SC	Annales de genetique	1998	PMID: 9599645

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 Dec 07, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs606231193 ...