ClinVar Genomic variation as it relates to human health

Variant summary: The PMM2 c.470T>C (p.Phe157Ser) variant causes a missense mutation involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome, which functional studies support this prediction. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 33/121274 (1/3675), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMM2 variant of 1/178. (0.0055902). The variant of interest has been reported in multiple affected individuals via publications, along with a reputable clinical laboratory citing the variant as "likely pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic.

DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.470T>C, in exon 6 that results in an amino acid change, p.Phe157Ser. This sequence change has been described in the gnomAD database with a frequency of 0.06% in the non-Finnish European subpopulation (dbSNP rs190521996). This sequence change has been described in the compound heterozygous state with other pathogenic/likely pathogenic variants in individuals with PMM2-related disorder (PMIDs: 24739649, 15645285, 11156536, 19357119, 25355454, 22012410). The p.Phe157Ser change affects a highly conserved amino acid residue located in the cap domain of the PMM2 protein. The p.Phe157Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies suggest p.Phe157Ser disrupts the stability and activity of the PMM2 protein (PMID: 21541725). Collectively, this evidence suggests p.Phe157Ser is likely pathogenic.

PS3, PS4, PM2, PM3_strong, PP3, PP4

PS3, PM3_Strong, PP3

Published functional studies demonstrate this variant results in complete loss of enzyme activity and may impact the stability and/or structure of the protein (Romano et al., 2009; Vega et al., 2011); 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: 17166182, 15844218, 15645285, 29482223, 11343337, 18948042, 19396570, 22012410, 19357119, 10527672, 11156536, 24739649, 28373276, 17920054, 12705494, 12607543, 23430838, 17158594, 25497157, 25355454, 21541725, 32304219, 32630370, 32841164, 33643843, 33413482, 31589614, 34598035, 33580824, 35279850, 33340551)

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ia (MIM#212065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The clinical manifestations and course are highly variable, ranging from infants who die in the first year of life to mildly affected adults. (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 91 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least twenty individuals with congenital disorder of glycosylation, including compound heterozygotes (PMID: 33340551). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

PMM2: PM3:Very Strong, PM2

Across a selection of the available literature, the PMM2 c.470T>C (p.Phe157Ser) missense variant is reported in a compound heterozygous state with a second variant in eight patients with congenital disorder of glycosylation type 1a (CDG1a), and in one patient where zygosity information is not provided (Matthijs et al. 1999; Briones et al. 2002; Noelle et al. 2005; Romano et al. 2009; Vega et al. 2011; Casado et al. 2012; Resende et al. 2014). Nearly all of these patients exhibited a severe phenotype and residual PMM2 enzyme activity in patient fibroblasts was extremely low or undetectable. Control data are unavailable for this variant, which is reported at a frequency of 0.00081 in the European American population of the Exome Sequencing Project. Analysis of the p.Phe157Ser variant in a prokaryotic expression system showed that the variant affected the stability and structure, and significantly decreased the half-life of the protein (Vega et al. 2011). Based on the collective evidence, the p.Phe157Ser variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

NM_000303.2(PMM2):c.470T>C(F157S) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 11156536, 17166182, 12607543, 12705494, 19396570, 17920054, 21541725 and 15645285. Classification of NM_000303.2(PMM2):c.470T>C(F157S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

ACMG classification criteria: PS3, PS4, PM3

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 157 of the PMM2 protein (p.Phe157Ser). This variant is present in population databases (rs190521996, gnomAD 0.06%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type Ia (PMID: 11156536, 15645285, 19357119, 21541725, 22012410, 24739649, 25355454). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188763). 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%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725). For these reasons, this variant has been classified as Pathogenic.

The PMM2 c.470T>C variant is predicted to result in the amino acid substitution p.Phe157Ser. This variant has been documented in many unrelated individuals to be causative for autosomal recessive congenital disorders of glycosylation type Ia due to abolished phosphomannomutase 2 enzyme activity (Matthijs et al. 1999. PubMed ID: 10527672; Vega et al. 2011. PubMed ID: 21541725; Resende et al. 2014. PubMed ID: 24739649). It has been interpreted as pathogenic or likely pathogenic by many independent submitters to ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/188763/). This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic.