Submissions for variant NM_001127178.3(PIGG):c.2086G>A (p.Glu696Lys)

gnomAD frequency: 0.00015  dbSNP: rs142598041

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537785	SCV000656877	uncertain significance	Intellectual disability, autosomal recessive 53	2022-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 696 of the PIGG protein (p.Glu696Lys). This variant is present in population databases (rs142598041, gnomAD 0.03%). 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: 476330). 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. 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.
Baylor Genetics	RCV000537785	SCV001528881	uncertain significance	Intellectual disability, autosomal recessive 53	2018-02-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001797106	SCV002038624	uncertain significance	not provided	2024-10-01	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002527923	SCV003597450	uncertain significance	Inborn genetic diseases	2021-10-12	criteria provided, single submitter	clinical testing	The c.2086G>A (p.E696K) alteration is located in exon 10 (coding exon 10) of the PIGG gene. This alteration results from a G to A substitution at nucleotide position 2086, causing the glutamic acid (E) at amino acid position 696 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics	RCV001797106	SCV005189958	uncertain significance	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV004755974	SCV005351275	uncertain significance	PIGG-related disorder	2024-06-10	no assertion criteria provided	clinical testing	The PIGG c.2086G>A variant is predicted to result in the amino acid substitution p.Glu696Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.025% of alleles in individuals of Latino descent in gnomAD. A variant affecting the same amino acid (c.2088G>C; p.Glu696Asp) has been reported in the compound heterozygous state with a second variant in the gene (c.2041C>T; p.Arg681Trp) in a patient with PIGG-related neurodevelopmental disease (Tremblay-Laganiere et al. 2021. PubMed ID: 34113002). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.