Submissions for variant NM_000311.5(PRNP):c.305C>T (p.Pro102Leu)

dbSNP: rs74315401

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203438	SCV001374604	pathogenic	Huntington disease-like 1	2024-09-21	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 13395). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRNP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRNP function (PMID: 8698234). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269667	SCV001449821	pathogenic	not provided	2015-10-12	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001642224	SCV001519189	pathogenic	Spongiform encephalopathy with neuropsychiatric features	2021-01-04	criteria provided, single submitter	research
DASA	RCV001813741	SCV002061168	pathogenic	Inherited Creutzfeldt-Jakob disease	2022-01-05	criteria provided, single submitter	clinical testing	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.
Genetic Services Laboratory, University of Chicago	RCV001269667	SCV002064352	pathogenic	not provided	2021-02-26	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV001813741	SCV002518906	pathogenic	Inherited Creutzfeldt-Jakob disease	2022-05-04	criteria provided, single submitter	clinical testing
OMIM	RCV000014329	SCV000034578	pathogenic	Gerstmann-Straussler-Scheinker syndrome	2002-07-05	no assertion criteria provided	literature only
GeneReviews	RCV000014329	SCV000040593	not provided	Gerstmann-Straussler-Scheinker syndrome		no assertion provided	literature only	Associated with Gerstmann-Straussler-Scheinker syndrome phenotype. One of the five most common variants that account for 85% of genetic prion disease.