chr20-4699525-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000311.5(PRNP):c.305C>T(p.Pro102Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,704 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P102P) has been classified as Likely benign.
Frequency
Consequence
NM_000311.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRNP | NM_000311.5 | c.305C>T | p.Pro102Leu | missense_variant | 2/2 | ENST00000379440.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRNP | ENST00000379440.9 | c.305C>T | p.Pro102Leu | missense_variant | 2/2 | 1 | NM_000311.5 | P1 | |
PRNP | ENST00000424424.2 | c.305C>T | p.Pro102Leu | missense_variant | 2/2 | 1 | P1 | ||
PRNP | ENST00000430350.2 | c.305C>T | p.Pro102Leu | missense_variant | 2/2 | 1 | P1 | ||
PRNP | ENST00000457586.2 | c.305C>T | p.Pro102Leu | missense_variant | 2/2 | 1 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461704Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727136
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 12, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 26, 2021 | DNA sequence analysis of the PRNP gene demonstrated a sequence change, c.305C>T, in exon 2 that results in an amino acid change, p.Pro102Leu. This sequence change is absent from the gnomAD general population database. This sequence change has been previously described in individuals and families with Gerstmann-Straussler disease (PMIDs: 2564168, 2572450, 2783132, 19696976). The p.Pro102Leu change affects a highly conserved amino acid residue of the PRNP protein. The p.Pro102Leu variant appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). Functional studies demonstrate cell lines with p.Pro102Leu result in decreased expression of normal prion protein and accumulation of abnormal prion protein on the cell surface (PMID: 11967261). Transgenic mice with p.Pro102Leu develop neurodegeneration (PMID: 8698234). These collective evidences indicate that this sequence change is pathogenic. - |
Inherited Creutzfeldt-Jakob disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.305C>T;p.(Pro102Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13395; OMIM: 176640.0002; PMID: 1672296; 2564168; 2572450; 2564168; 19696976; 22097954) - PS4.This variant is not present in population databases (rs74315401, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 22097954) - PM6. The variant co-segregated with disease in multiple affected family members (PMID: 1672296; 2564168; 2572450) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Gerstmann-Straussler-Scheinker syndrome Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 05, 2002 | - - |
not provided, no classification provided | literature only | GeneReviews | - | Associated with Gerstmann-Straussler-Scheinker syndrome phenotype. One of the five most common variants that account for 85% of genetic prion disease. - |
Huntington disease-like 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PRNP function (PMID: 8698234). 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 PRNP protein function. ClinVar contains an entry for this variant (Variation ID: 13395). This missense change has been observed in individual(s) with Gerstmann-Sträussler-Scheinker (GSS) syndrome (PMID: 2564168, 19696976, 22097954). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 102 of the PRNP protein (p.Pro102Leu). - |
Spongiform encephalopathy with neuropsychiatric features Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris | Jan 04, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at