rs74315401

Positions:

• chr20-4699525-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.06

Genes affected

PRNP (HGNC:9449): (prion protein (Kanno blood group)) The protein encoded by this gene is a membrane glycosylphosphatidylinositol-anchored glycoprotein that tends to aggregate into rod-like structures. The encoded protein contains a highly unstable region of five tandem octapeptide repeats. This gene is found on chromosome 20, approximately 20 kbp upstream of a gene which encodes a biochemically and structurally similar protein to the one encoded by this gene. Mutations in the repeat region as well as elsewhere in this gene have been associated with Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Straussler disease, Huntington disease-like 1, and kuru. An overlapping open reading frame has been found for this gene that encodes a smaller, structurally unrelated protein, AltPrp. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 20-4699525-C-T is Pathogenic according to our data. Variant chr20-4699525-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699525-C-T is described in UniProt as null. Variant chr20-4699525-C-T is described in UniProt as null. Variant chr20-4699525-C-T is described in UniProt as null. Variant chr20-4699525-C-T is described in UniProt as null. Variant chr20-4699525-C-T is described in UniProt as null. Variant chr20-4699525-C-T is described in UniProt as null. Variant chr20-4699525-C-T is described in Lovd as [Pathogenic]. Variant chr20-4699525-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5	c.305C>T	p.Pro102Leu	missense_variant	2/2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9	c.305C>T	p.Pro102Leu	missense_variant	2/2	1	NM_000311.5	ENSP00000368752.4
PRNP	ENST00000424424.2	c.305C>T	p.Pro102Leu	missense_variant	2/2	1		ENSP00000411599.2
PRNP	ENST00000430350.2	c.305C>T	p.Pro102Leu	missense_variant	2/2	1		ENSP00000399376.2
PRNP	ENST00000457586.2	c.305C>T	p.Pro102Leu	missense_variant	2/2	1		ENSP00000415284.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461704 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 12, 2015	- -

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:1 Other: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

Labcorp Genetics (formerly Invitae), Labcorp

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.79
MutPred		0.86		Loss of glycosylation at P102 (P = 0.0217);Loss of glycosylation at P102 (P = 0.0217);Loss of glycosylation at P102 (P = 0.0217);Loss of glycosylation at P102 (P = 0.0217);
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74315401; hg19: chr20-4680171;