16-8847797-G-C
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000303.3(PMM2):āc.713G>Cā(p.Arg238Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,530 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R238G) 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 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PMM2 | NM_000303.3 | c.713G>C | p.Arg238Pro | missense_variant | Exon 8 of 8 | ENST00000268261.9 | NP_000294.1 | |
PMM2 | XM_047434215.1 | c.464G>C | p.Arg155Pro | missense_variant | Exon 6 of 6 | XP_047290171.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250978Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135690
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461332Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726998
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
PMM2-congenital disorder of glycosylation Pathogenic:3
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 238 of the PMM2 protein (p.Arg238Pro). This variant is present in population databases (rs151319324, gnomAD 0.006%). This missense change has been observed in individual(s) with congenital disorder of glycosylation Ia (PMID: 10066032, 25681648). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1333592). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMM2 protein function. For these reasons, this variant has been classified as Pathogenic. -
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMM2 related disorder (PMID:9497260, PS1_P). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25681648, PM3_M). A different missense change at the same codon has been reported to be associated with PMM2 related disorder (PMID:11058895, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.723, PP3_P). A missense variant is a common mechanism associated with Congenital disorder of glycosylation (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at