Submissions for variant NM_032634.4(PIGO):c.1723T>G (p.Phe575Val)

gnomAD frequency: 0.00002  dbSNP: rs769087057

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001751947	SCV001986637	uncertain significance	not provided	2020-09-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016)
Invitae	RCV002539915	SCV003492510	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2022-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 575 of the PIGO protein (p.Phe575Val). This variant is present in population databases (rs769087057, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PIGO-related conditions. ClinVar contains an entry for this variant (Variation ID: 1304180). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV002539915	SCV004037343	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2020-01-24	criteria provided, single submitter	clinical testing	The c.1723T>G variant in the PIGO gene is a missense variant which results in the substitution of a conserved phenylalanine residue at amino acid position 575 for a valine (NP_116023.2). This variant localizes to coding exon 7 of the PIGO gene (11 coding exons in total; NM_032634.4). It is predicted to be damaging to protein structure and/or function by PROVEAN and SIFT. This variant is present in the Genome Aggregation Database (gnomAD) at a very low frequency, 0.00199% (5 out of 251,270 alleles), indicating it is not a common benign variant in the populations represented in this database. To the best of our knowledge, this specific variant has not been reported in the literature or any human disease mutation databases. Given this evidence, the c.1723T>G, p.Phe575Val variant in PIGO is classified as a variant of uncertain clinical significance. Parental studies were not conducted at our laboratory, but this variant was reported at another laboratory to be maternally inherited in a separate pregnancy with same parents (2019)
PreventionGenetics, part of Exact Sciences	RCV003407788	SCV004114441	uncertain significance	PIGO-related disorder	2022-10-13	criteria provided, single submitter	clinical testing	The PIGO c.1723T>G variant is predicted to result in the amino acid substitution p.Phe575Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-35092161-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.