rs150719105
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 19P and 1B. PS1PM1PM2PM5PP3PP5_Very_StrongBP4
The NM_000303.3(PMM2):c.430T>C(p.Phe144Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000338 in 1,566,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F144V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000303.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMM2 | NM_000303.3 | c.430T>C | p.Phe144Leu | missense_variant | 5/8 | ENST00000268261.9 | |
PMM2 | XM_047434215.1 | c.181T>C | p.Phe61Leu | missense_variant | 3/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMM2 | ENST00000268261.9 | c.430T>C | p.Phe144Leu | missense_variant | 5/8 | 1 | NM_000303.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152154Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000165 AC: 31AN: 188306Hom.: 0 AF XY: 0.000119 AC XY: 12AN XY: 100472
GnomAD4 exome AF: 0.0000290 AC: 41AN: 1414502Hom.: 0 Cov.: 30 AF XY: 0.0000228 AC XY: 16AN XY: 700236
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152272Hom.: 0 Cov.: 34 AF XY: 0.0000806 AC XY: 6AN XY: 74454
ClinVar
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:6
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Apr 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 30, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 30, 2022 | 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. This frequency is not significantly higher than estimated for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (0.00016 vs 0.0056), allowing no conclusion about variant significance. c.430T>C has been reported in the literature as a compound heterozygous genotype in individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, At Teneji_2017, Kondo_1999). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 06, 2022 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 28, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2016 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at