Submissions for variant NM_176787.5(PIGN):c.2354G>A (p.Arg785His)

gnomAD frequency: 0.00004  dbSNP: rs535563062

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000430866	SCV000514117	likely pathogenic	not provided	2021-12-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33619735)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001343035	SCV001536991	likely pathogenic	Multiple congenital anomalies-hypotonia-seizures syndrome 1	2025-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 785 of the PIGN protein (p.Arg785His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of PIGN-congenital disorder of glycosylation (PMID: 33619735, 35179230; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 378363). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PIGN protein function with a positive predictive value of 80%. This variant disrupts the p.Arg785 amino acid residue in PIGN. Other variant(s) that disrupt this residue have been observed in individuals with PIGN-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001343035	SCV002764824	likely pathogenic	Multiple congenital anomalies-hypotonia-seizures syndrome 1	2020-08-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000430866	SCV001809176	uncertain significance	not provided		flagged submission	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000430866	SCV001971537	uncertain significance	not provided		flagged submission	clinical testing
Ambry Genetics	RCV002446654	SCV002733134	uncertain significance	Inborn genetic diseases	2017-06-21	flagged submission	clinical testing	The p.R785H variant (also known as c.2354G>A), located in coding exon 22 of the PIGN gene, results from a G to A substitution at nucleotide position 2354. The arginine at codon 785 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as paternally inherited in an individual with dysmorphic features, seizures, developmental delay, and hypotonia, who also had a second maternally inherited PIGN alteration ([Abstract p.24]; Abstract presented at: 27th European Meeting on Dysmorphology; 2016 September 7-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.