Submissions for variant NM_001346754.2(PIGW):c.106A>G (p.Arg36Gly)

gnomAD frequency: 0.00031  dbSNP: rs142067039

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519253	SCV000621125	uncertain significance	not provided	2024-05-12	criteria provided, single submitter	clinical testing	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: 34426522, 32198969, 36740579, 30679815, 35788948, Savasan2023[casereport])
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858026	SCV002153994	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 5	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 36 of the PIGW protein (p.Arg36Gly). This variant is present in population databases (rs142067039, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of PIGW-related conditions (PMID: 30679815). ClinVar contains an entry for this variant (Variation ID: 452328). 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 PIGW protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001858026	SCV002767542	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 5	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (62 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygote). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been reported as homozygous and likely pathogenic in a family with 2 foetuses with Fryns or Fryns-like syndrome (PMID:30679815). It has also been reported as a VUS in ClinVar. (P) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Ambry Genetics	RCV002525234	SCV003692919	uncertain significance	Inborn genetic diseases	2022-06-02	criteria provided, single submitter	clinical testing	The c.106A>G (p.R36G) alteration is located in exon 2 (coding exon 1) of the PIGW gene. This alteration results from a A to G substitution at nucleotide position 106, causing the arginine (R) at amino acid position 36 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000519253	SCV004144487	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	PIGW: BP4
OMIM	RCV001858026	SCV002570120	pathogenic	Hyperphosphatasia with intellectual disability syndrome 5	2022-09-09	no assertion criteria provided	literature only