20-4699813-T-C

Position:

• chr20-4699813-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000311.5(PRNP):​c.593T>C​(p.Phe198Ser) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.35

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.

• PM1: In a strand (size 6) in uniprot entity PRIO_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000311.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 20-4699813-T-C is Pathogenic according to our data. Variant chr20-4699813-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699813-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5	c.593T>C	p.Phe198Ser	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.593T>C	p.Phe198Ser	missense_variant	2/2	1	NM_000311.5	ENSP00000368752	P1
PRNP	ENST00000424424.2	c.593T>C	p.Phe198Ser	missense_variant	2/2	1		ENSP00000411599	P1
PRNP	ENST00000430350.2	c.593T>C	p.Phe198Ser	missense_variant	2/2	1		ENSP00000399376	P1
PRNP	ENST00000457586.2	c.593T>C	p.Phe198Ser	missense_variant	2/2	1		ENSP00000415284	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 14, 2022

Published functional studies demonstrate a damaging effect through thermodynamic instability and aggregation of the protein (Liemann et al., 1999; Singh et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8939199, 20301407, 16939293, 14761942, 21875156, 21689662, 20541558, 20932979, 21552571, 19680558, 19543376, 25959220, 29338055, 12372829, 7954833, 1363810, 1363809, 30877692, 31890235, 32560489, 31340582, 10079068, 8105481) -

Huntington disease-like 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 14, 2017

This sequence change replaces phenylalanine with serine at codon 198 of the PRNP protein (p.Phe198Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with disease in a large and extensively studied family, referred to as the 'Indiana kindred', affected with Gerstmann-Straussler-Scheinker disease (GSS) (PMID: 1363810, 1363809). ClinVar contains an entry for this variant (Variation ID: 13401). Numerous experimental studies in vivo and in vitro have shown that this missense change (p.Phe198Ser) disrupts proper PRNP protein structure, folding, stability, and function (PMID: 16939293, 20541558, 25959220, 10079068, 12372829, 8939199). For these reasons, this variant has been classified as Pathogenic. -

Gerstmann-Straussler-Scheinker syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 13, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.97	.;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.7	M;M;.;.
MutationTaster	Benign	0.88	A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.79	N;N;N;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.75
MutPred		0.85		Gain of disorder (P = 0.0161);Gain of disorder (P = 0.0161);Gain of disorder (P = 0.0161);Gain of disorder (P = 0.0161);
MVP		1.0
MPC		1.8
ClinPred		0.85	D
GERP RS		5.4
Varity_R		0.72
gMVP		0.90

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: rs74315405; hg19: chr20-4680459;