rs80338706
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000303.3(PMM2):āc.677C>Gā(p.Thr226Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,694 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 Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T226I) 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.677C>G | p.Thr226Ser | missense_variant | 8/8 | ENST00000268261.9 | |
PMM2 | XM_047434215.1 | c.428C>G | p.Thr143Ser | missense_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMM2 | ENST00000268261.9 | c.677C>G | p.Thr226Ser | missense_variant | 8/8 | 1 | NM_000303.3 | P1 | |
ENST00000567942.1 | n.319G>C | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251300Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135846
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461694Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727166
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:4Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 01, 2022 | Variant summary: PMM2 c.677C>G (p.Thr226Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251300 control chromosomes. c.677C>G has been reported in the literature as compound heterozygous genotypes in individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Vuillaumier-Barrot_2000, de Lonlay_2001, Briones_2002, Quelhas_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function example, Vuillaumier-Barrot_2000). The most pronounced variant effect results in 10%-<30% of normal Phosphomannomutase enzyme activity in-vitro. 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 22, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2021 | Experimental studies have shown that this missense change affects PMM2 function (PMID: 10922383). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). ClinVar contains an entry for this variant (Variation ID: 7722). This missense change has been observed in individual(s) with PMM2-related conditions (PMID: 10922383, 11156536, 17166182). This variant is present in population databases (rs80338706, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 226 of the PMM2 protein (p.Thr226Ser). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at