Submissions for variant NM_032634.4(PIGO):c.2287G>T (p.Val763Leu)

gnomAD frequency: 0.00009  dbSNP: rs146576650

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000419926	SCV000529968	uncertain significance	not provided	2023-09-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000697576	SCV000826196	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 763 of the PIGO protein (p.Val763Leu). This variant is present in population databases (rs146576650, 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: 387821). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Illumina Laboratory Services, Illumina	RCV000697576	SCV001331021	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2018-03-30	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002522397	SCV003704781	uncertain significance	Inborn genetic diseases	2022-12-21	criteria provided, single submitter	clinical testing	The c.2287G>T (p.V763L) alteration is located in exon 7 (coding exon 6) of the PIGO gene. This alteration results from a G to T substitution at nucleotide position 2287, causing the valine (V) at amino acid position 763 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.