Submissions for variant NM_002435.3(MPI):c.1178G>C (p.Gly393Ala)

gnomAD frequency: 0.00019  dbSNP: rs201815588

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000549138	SCV000393955	uncertain significance	MPI-congenital disorder of glycosylation	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549138	SCV000645196	uncertain significance	MPI-congenital disorder of glycosylation	2022-06-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 393 of the MPI protein (p.Gly393Ala). This variant is present in population databases (rs201815588, gnomAD 0.1%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1b (PMID: 32905087). ClinVar contains an entry for this variant (Variation ID: 317143). 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 disruptive. 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.
Baylor Genetics	RCV000549138	SCV001529855	uncertain significance	MPI-congenital disorder of glycosylation	2018-08-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV003235190	SCV003932974	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing	Observed with a second MPI variant but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes; this individual is reported with teenage-onset cerebral venous sinus thrombosis as the first and only presenting symptom followed by absent mannose phosphate isomerase activity in leukocytes (Mhlhausen C et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32905087)
Natera, Inc.	RCV000549138	SCV002089794	uncertain significance	MPI-congenital disorder of glycosylation	2020-02-21	no assertion criteria provided	clinical testing