Submissions for variant NM_176787.5(PIGN):c.1694G>T (p.Arg565Leu)

dbSNP: rs201835155

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418646	SCV000534047	likely pathogenic	not provided	2023-10-15	criteria provided, single submitter	clinical testing	Reported in a patient with features consistent with a PIGN-related disorder who had a second PIGN variant in trans (PMID: 32220244); Not observed at significant frequency in large population cohorts (gnomAD); 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: Xiuwei_2021, 32220244)
Invitae	RCV000695519	SCV000824025	pathogenic	Multiple congenital anomalies-hypotonia-seizures syndrome 1	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 565 of the PIGN protein (p.Arg565Leu). 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-related conditions (PMID: 32220244, 35322241; Invitae). 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: 391067). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIGN protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000695519	SCV001530670	uncertain significance	Multiple congenital anomalies-hypotonia-seizures syndrome 1	2018-07-19	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Centogene AG - the Rare Disease Company	RCV000695519	SCV002059818	uncertain significance	Multiple congenital anomalies-hypotonia-seizures syndrome 1	2019-06-20	criteria provided, single submitter	clinical testing
Mendelics	RCV002248660	SCV002519123	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411404	SCV002715417	uncertain significance	Inborn genetic diseases	2017-10-13	criteria provided, single submitter	clinical testing	The p.R565L variant (also known as c.1694G>T), located in coding exon 16 of the PIGN gene, results from a G to T substitution at nucleotide position 1694. The arginine at codon 565 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000418646	SCV004143215	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PIGN: PM2, PM3