Submissions for variant NM_032634.4(PIGO):c.626A>G (p.Asn209Ser)

gnomAD frequency: 0.00084  dbSNP: rs138028827

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001086092	SCV000479880	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 2	2018-01-12	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.
Invitae	RCV001086092	SCV000652707	likely benign	Hyperphosphatasia with intellectual disability syndrome 2	2024-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000539232	SCV001155635	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000539232	SCV001768314	uncertain significance	not provided	2023-03-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 36762943)
PreventionGenetics, part of Exact Sciences	RCV003902437	SCV004723461	likely benign	PIGO-related disorder	2019-12-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586694	SCV005076118	uncertain significance	not specified	2024-04-16	criteria provided, single submitter	clinical testing	Variant summary: PIGO c.626A>G (p.Asn209Ser) results in a conservative amino acid change located in the GPI ethanolamine phosphate transferase 3, N-terminal domain (IPR037675) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 238830 control chromosomes. c.626A>G has been reported in the literature in an individual affected with atypical femur fracture (e.g. Marini_2023). This report do not provide unequivocal conclusions about association of the variant with Hyperphosphatasia With Intellectual Disability Syndrome 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36762943). ClinVar contains an entry for this variant (Variation ID: 366761). Based on the evidence outlined above, the variant was classified as uncertain significance.