Submissions for variant NM_000303.3(PMM2):c.91T>C (p.Phe31Leu)

gnomAD frequency: 0.00005  dbSNP: rs749720760

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000487831	SCV000575034	likely pathogenic	not provided	2016-11-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000487831	SCV000862509	uncertain significance	not provided	2018-07-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780613	SCV000918031	uncertain significance	not specified	2022-10-15	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.91T>C (p.Phe31Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 248014 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (7.7e-05 vs 0.0056), allowing no conclusion about variant significance. c.91T>C has been reported in the literature as a novel variant in one individual affected with Congenital Disorder of Glycosylation Type 1a with elevated levels of asialotransferrin and disialotransferrin, and low tetrasialotransferrin (Teneiji_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000675084	SCV001210743	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the PMM2 protein (p.Phe31Leu). This variant is present in population databases (rs749720760, gnomAD 0.02%). This missense change has been observed in individual(s) with PMM2-congenital disorder of glycosylation (PMM2-CDG) (PMID: 28122681). ClinVar contains an entry for this variant (Variation ID: 425093). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV000675084	SCV002060328	uncertain significance	PMM2-congenital disorder of glycosylation	2021-11-03	criteria provided, single submitter	clinical testing	NM_000303.2(PMM2):c.91T>C(F31L) is a missense variant classified as a variant of uncertain significance in the context of congenital disorder of glycosylation type Ia. F31L has been observed in a case with relevant disease (PMID 28122681). Functional assessments of this variant are not available in the literature. F31L has been observed in population frequency databases (gnomAD: AMR 0.02%). In summary, there is insufficient evidence to classify NM_000303.2(PMM2):c.91T>C(F31L) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV000675084	SCV004205254	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-03-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000675084	SCV001457163	uncertain significance	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing