rs80338732
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_002764.4(PRPS1):c.344T>C(p.Met115Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M115V) has been classified as Pathogenic.
Frequency
Consequence
NM_002764.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRPS1 | NM_002764.4 | c.344T>C | p.Met115Thr | missense_variant | 3/7 | ENST00000372435.10 | |
PRPS1 | NM_001204402.2 | c.-82-4238T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRPS1 | ENST00000372435.10 | c.344T>C | p.Met115Thr | missense_variant | 3/7 | 1 | NM_002764.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease X-linked recessive 5 Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2007 | - - |
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 115 of the PRPS1 protein (p.Met115Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5) (PMID: 17701900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9935). 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 not expected to disrupt PRPS1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRPS1 function (PMID: 17701900, 33493137). This variant disrupts the p.Met115 amino acid residue in PRPS1. Other variant(s) that disrupt this residue have been observed in individuals with PRPS1-related conditions (PMID: 25182139), which suggests that this may be a clinically significant amino acid residue. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at