Submissions for variant NM_032634.4(PIGO):c.1297C>T (p.Arg433Trp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002472218	SCV002769310	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_032634.2(PIGO):c.1297C>T in exon 7 of 11 of the PIGO gene. This substitution is predicted to create a major amino acid change from an arginine to a tryptophan at position 433 of the protein; NP_116023.2(PIGO):p.(Arg433Trp). The arginine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain (NCBI, PDB). In silico software predictions of the pathogenicity of this variant are conflicting (PolyPhen2, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.00040% (1 heterozygote, 0 homozygotes). This variant has not previously been reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VUS. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002472218	SCV003260181	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2022-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 433 of the PIGO protein (p.Arg433Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PIGO-related conditions. 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: "Benign"; Align-GVGD: "Class C0"). 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.