rs768021123
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000303.3(PMM2):βc.24delβ(p.Cys9AlafsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,611,362 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L8L) has been classified as Likely benign.
Frequency
Consequence
NM_000303.3 frameshift
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.24del | p.Cys9AlafsTer27 | frameshift_variant | 1/8 | ENST00000268261.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMM2 | ENST00000268261.9 | c.24del | p.Cys9AlafsTer27 | frameshift_variant | 1/8 | 1 | NM_000303.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000166 AC: 4AN: 241614Hom.: 0 AF XY: 0.0000228 AC XY: 3AN XY: 131720
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1459154Hom.: 0 Cov.: 32 AF XY: 0.0000262 AC XY: 19AN XY: 725746
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:6
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Apr 04, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Cys9Alafs*27) in the PMM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). This variant is present in population databases (rs768021123, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with congenital disorder of glycosylation (PMID: 11058895, 12297897, 18093857, 19168813). ClinVar contains an entry for this variant (Variation ID: 188744). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 27, 2018 | Variant summary: PMM2 c.24delC (p.Cys9AlafsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.7e-05 in 236838 control chromosomes. c.24delC has been reported in the literature in individuals affected with Congenital Disorder of Glycosylation Type 1a (Arnoux_2008, Le Bizec_2005, Schollen_2002, Westphal_2001). 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, which showed the variant to have <10% enzyme activity in a yeast expression system (Westphal_2001). 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 pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2024 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 11, 2023 | Published functional studies demonstrate a damaging effect of reduction of PMM activity to negative control level (PMID: 11715002); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12297897, 12529711, 11058895, 18093857, 33643843, 19168813, 11715002, 15844218) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | PMM2: PM3:Strong, PVS1:Strong, PM2 - |
PMM2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 27, 2022 | The PMM2 c.24delC variant is predicted to result in a frameshift and premature protein termination (p.Cys9Alafs*27). This variant has been reported in individuals with autosomal recessive congenital disorder of glycosylation 1a (Matthijs et al. 2000. PubMed ID: 11058895; Jamroz et al. 2009. PubMed ID: 19168813; Westphal et al. 2001. PubMed ID: 11715002). This variant is reported in 0.0037% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-8891762-TC-T). Frameshift variants in PMM2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at