Submissions for variant NM_001127178.3(PIGG):c.641A>G (p.His214Arg)

gnomAD frequency: 0.00002  dbSNP: rs782157451

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002472007	SCV002767723	likely pathogenic	Intellectual disability, autosomal recessive 53	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy (MIM#616917). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated phosphodiest domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A homozygous change to tyrosine has been identified in an individual with severe intellectual disability, moderate developmental delay, hypotonia and absent Emm expression (ClinVar; PMID: 33763700). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been regarded as a VUS by a clinical laboratory (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a pathogenic heterozygous variant (NM_001127178.2(PIGG):c.1956G>A; p.(Trp652*)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002472007	SCV003215398	uncertain significance	Intellectual disability, autosomal recessive 53	2024-06-03	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 214 of the PIGG protein (p.His214Arg). This variant is present in population databases (rs782157451, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PIGG-related conditions. ClinVar contains an entry for this variant (Variation ID: 1805589). 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 PIGG protein function with a positive predictive value of 80%. 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.