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

gnomAD frequency: 0.00005  dbSNP: rs749720760

Total submissions: 10

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	RCV000675084	SCV000918031	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-11-04	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. This frequency is not significantly higher than estimated 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 in individuals affected with Congenital Disorder Of Glycosylation Type 1a or Primary Ovarian Insufficiency. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 425093). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000675084	SCV001210743	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-12-06	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-related conditions (PMID: 28122681, 33921431). ClinVar contains an entry for this variant (Variation ID: 425093). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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
GeneDx	RCV000487831	SCV005326065	likely pathogenic	not provided	2024-02-05	criteria provided, single submitter	clinical testing	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: 34859900, 28122681, 33921431, 28820871)
Fulgent Genetics, Fulgent Genetics	RCV000675084	SCV005641525	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-02-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000675084	SCV005877279	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-10-11	criteria provided, single submitter	clinical testing	The PMM2 c.91T>C; p.Phe31Leu variant (rs749720760, ClinVar Variation ID: 425093) is reported in the literature in multiple individual with suspicion for congenital disorders of glycosylation, or related clinical presentations (Al Teneiji 2017, Arteche-Lopez 2021, Heddar 2022). This variant is found in the Admixed American population with an allele frequency of 0.02% (7/34558 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.764). Based on available information, this variant is considered to be likely pathogenic. References: Al Teneiji A et al. Phenotypic and genotypic spectrum of congenital disorders of glycosylation type I and type II. Mol Genet Metab. 2017 Mar;120(3):235-242. PMID: 28122681. Arteche-Lopez A et al. Towards a Change in the Diagnostic Algorithm of Autism Spectrum Disorders: Evidence Supporting Whole Exome Sequencing as a First-Tier Test. Genes (Basel). 2021 Apr 12;12(4):560. PMID: 33921431 Heddar A et al. Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine. EBioMedicine. 2022 Oct;84:104246. PMID: 36099812
Natera, Inc.	RCV000675084	SCV001457163	uncertain significance	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing