rs532870929
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000303.3(PMM2):c.620T>C(p.Phe207Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,603,480 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 (★★). Synonymous variant affecting the same amino acid position (i.e. F207F) has been classified as Likely benign.
Frequency
Consequence
NM_000303.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMM2 | NM_000303.3 | c.620T>C | p.Phe207Ser | missense_variant | 7/8 | ENST00000268261.9 | |
PMM2 | XM_047434215.1 | c.371T>C | p.Phe124Ser | missense_variant | 5/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMM2 | ENST00000268261.9 | c.620T>C | p.Phe207Ser | missense_variant | 7/8 | 1 | NM_000303.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251474Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135908
GnomAD4 exome AF: 0.0000200 AC: 29AN: 1451116Hom.: 0 Cov.: 28 AF XY: 0.0000166 AC XY: 12AN XY: 722814
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152364Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74504
ClinVar
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2023 | Variant summary: PMM2 c.620T>C (p.Phe207Ser) 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 3.6e-05 in 251474 control chromosomes. c.620T>C has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (eg. Cabezas_2017, Francisco_2020, Parrado_2022, etc). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Vega_2011). Four 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 pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 22, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 207 of the PMM2 protein (p.Phe207Ser). This variant is present in population databases (rs532870929, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type Ia or with related clinical features (PMID: 12705494, 19396570, 21541725, 28373276). ClinVar contains an entry for this variant (Variation ID: 189141). 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%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 06, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 19, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at