Submissions for variant NM_001127178.3(PIGG):c.2552A>C (p.Gln851Pro)

gnomAD frequency: 0.00014  dbSNP: rs150802299

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481105	SCV000569970	likely pathogenic	not provided	2023-06-06	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: 34113002)
Invitae	RCV001043680	SCV001207438	likely pathogenic	Intellectual disability, autosomal recessive 53	2023-09-24	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects PIGG function (PMID: 34113002). 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. ClinVar contains an entry for this variant (Variation ID: 420935). This missense change has been observed in individual(s) with PIGG-related conditions (PMID: 34113002). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs150802299, gnomAD 0.03%). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 851 of the PIGG protein (p.Gln851Pro).
Baylor Genetics	RCV001043680	SCV001528886	uncertain significance	Intellectual disability, autosomal recessive 53	2018-01-27	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001043680	SCV004122009	likely pathogenic	Intellectual disability, autosomal recessive 53	2023-10-23	criteria provided, single submitter	clinical testing	Variant summary: PIGG c.2552A>C (p.Gln851Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250846 control chromosomes. c.2552A>C has been reported in the literature in compound heterozygous and homozygous individuals affected with Intellectual Disability, Autosomal Recessive associated with GPI deficiency (e.g. Tremblay-Laganiere_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reportedly null enzyme activity (e.g.Tremblay-Laganiere_2021). The following publication has been ascertained in the context of this evaluation (PMID: 34113002). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as likely pathogenic (n=2), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.