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

dbSNP: rs606231193

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008093	SCV001167838	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing	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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000011726	SCV002525446	pathogenic	Renpenning syndrome		criteria provided, single submitter	research
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000011726	SCV002559194	pathogenic	Renpenning syndrome		criteria provided, single submitter	clinical testing
Molecular Genetics Lab, CHRU Brest	RCV000011726	SCV004697775	pathogenic	Renpenning syndrome		criteria provided, single submitter	clinical testing
OMIM	RCV000011726	SCV000031958	pathogenic	Renpenning syndrome	2003-12-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004745153	SCV005355139	pathogenic	PQBP1-related disorder	2024-09-11	no assertion criteria provided	clinical testing	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.