Submissions for variant NM_032634.4(PIGO):c.1864C>A (p.Leu622Met)

gnomAD frequency: 0.00006  dbSNP: rs149262338

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000686480	SCV000813999	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2022-07-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 622 of the PIGO protein (p.Leu622Met). This variant is present in population databases (rs149262338, 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: 566617). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Illumina Laboratory Services, Illumina	RCV000686480	SCV001429899	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2018-01-13	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.
GeneDx	RCV001662749	SCV001874780	uncertain significance	not provided	2021-08-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24417746)
Ambry Genetics	RCV003278988	SCV003959307	uncertain significance	Inborn genetic diseases	2023-03-22	criteria provided, single submitter	clinical testing	The c.1864C>A (p.L622M) alteration is located in exon 7 (coding exon 6) of the PIGO gene. This alteration results from a C to A substitution at nucleotide position 1864, causing the leucine (L) at amino acid position 622 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.