Submissions for variant NM_000303.3(PMM2):c.430T>C (p.Phe144Leu)

gnomAD frequency: 0.00006  dbSNP: rs150719105

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414479	SCV000490727	likely pathogenic	not provided	2016-11-18	criteria provided, single submitter	clinical testing	The F144L variant has previously been reported in unrelated individuals with congenital disorder of glycosylation type 1a (CDG-1a) who were heterozygous for F144L and another missense variant in the PMM2 gene, although the phase of these variants was not reported (Kondo et al., 1999; Kane et al., 2016). The 1000 Genomes Project Consortium reports F144L was observed in 2/1008 alleles from individuals of East Asian background. The F144L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E139K, R141H, D148N) have been reported in the Human Gene Mutation Database in association with CDG-1a (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Eurofins Ntd Llc (ga)	RCV000414479	SCV000700607	likely pathogenic	not provided	2017-04-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000596795	SCV000965006	pathogenic	PMM2-congenital disorder of glycosylation	2024-01-11	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 144 of the PMM2 protein (p.Phe144Leu). This variant is present in population databases (rs150719105, gnomAD 0.2%). This missense change has been observed in individual(s) with PMM2-related disease (PMID: 10066032, 28122681, 30687093). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197658). 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%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000596795	SCV001163403	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-03-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000596795	SCV002024687	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000596795	SCV002570573	pathogenic	PMM2-congenital disorder of glycosylation	2024-06-07	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.430T>C (p.Phe144Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 188306 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (0.0056), allowing no conclusion about variant significance. c.430T>C has been reported in the literature in multiple compound heterozygous individuals affected with Congenital Disorder Of Glycosylation Type 1a (e.g. Kondo_1999, At Teneji_2017, Wang 2019, Lin 2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28122681, 32635232, 10066032, 10392743, 33176815, 30687093). ClinVar contains an entry for this variant (Variation ID: 197658). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000596795	SCV002807072	pathogenic	PMM2-congenital disorder of glycosylation	2022-04-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000596795	SCV000800756	likely pathogenic	PMM2-congenital disorder of glycosylation	2017-04-18	no assertion criteria provided	clinical testing