16-8811161-T-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000303.3(PMM2):āc.430T>Gā(p.Phe144Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,414,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F144L) has been classified as Pathogenic.
Frequency
Consequence
NM_000303.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PMM2 | NM_000303.3 | c.430T>G | p.Phe144Val | missense_variant | Exon 5 of 8 | ENST00000268261.9 | NP_000294.1 | |
PMM2 | XM_047434215.1 | c.181T>G | p.Phe61Val | missense_variant | Exon 3 of 6 | XP_047290171.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome AF: 0.0000113 AC: 16AN: 1414502Hom.: 0 Cov.: 30 AF XY: 0.0000129 AC XY: 9AN XY: 700236
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:1
This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 144 of the PMM2 protein (p.Phe144Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMM2-related conditions. 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. This variant disrupts the p.Phe144 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10066032, 28122681, 30687093). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
not specified Uncertain:1
Variant summary: PMM2 c.430T>G (p.Phe144Val) 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 188306 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.430T>G in individuals affected with Congenital Disorder Of Glycosylation Type 1a and no experimental evidence demonstrating its impact on protein function have been reported. However, a different variant located at the same codon has been classified as likley pathogenic/pathogenic by multiple clinvar submitters (p.Phe144Leu). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.