16-8812994-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Moderate
The NM_000303.3(PMM2):c.527G>T(p.Gly176Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.
Frequency
Consequence
NM_000303.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PMM2 | NM_000303.3 | c.527G>T | p.Gly176Val | missense_variant | Exon 7 of 8 | ENST00000268261.9 | NP_000294.1 | |
PMM2 | XM_047434215.1 | c.278G>T | p.Gly93Val | missense_variant | Exon 5 of 6 | XP_047290171.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:1
Variant summary: PMM2 c.527G>T (p.Gly176Val) 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 was absent in 251478 control chromosomes. c.527G>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Congenital Disorder Of Glycosylation Type 1a (example, LeBizec_2005) based on clinical manifestations, confirmed by western blot patterns of serum N-glycoproteins (transferrin, alpha1 transferrin, haptoglobin, alpha1-acid glycoprotein) and deficient cellular activity of phosphomannomutase in leukocytes and/or cultured fibroblasts from forearm biopsy. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal PMM2 enzyme activity activity in an E Coli expression system (LeBizec_2005). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.