rs398122413

Positions:

• chr20-4699853-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000311.5(PRNP):​c.633G>C​(p.Glu211Asp) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E211Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 0.977

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a disulfide_bond (size 35) in uniprot entity PRIO_HUMAN there are 12 pathogenic changes around while only 3 benign (80%) in NM_000311.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-4699851-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5	c.633G>C	p.Glu211Asp	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.633G>C	p.Glu211Asp	missense_variant	2/2	1	NM_000311.5	ENSP00000368752	P1
PRNP	ENST00000424424.2	c.633G>C	p.Glu211Asp	missense_variant	2/2	1		ENSP00000411599	P1
PRNP	ENST00000430350.2	c.633G>C	p.Glu211Asp	missense_variant	2/2	1		ENSP00000399376	P1
PRNP	ENST00000457586.2	c.633G>C	p.Glu211Asp	missense_variant	2/2	1		ENSP00000415284	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gerstmann-Straussler-Scheinker syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 2012

- -

Huntington disease-like 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Glu211 amino acid residue in PRNP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10790216, 11568919, 12590162, 22965875). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 88922). This variant is also known as c.633C>G. This missense change has been observed in individuals with clinical features of PRNP-related conditions (PMID: 22965875; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 211 of the PRNP protein (p.Glu211Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.7	M;M;.;.
MutationTaster	Benign	0.54	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		0.0040	B;B;.;.
Vest4		0.65
MutPred		0.79		Loss of disorder (P = 0.1828);Loss of disorder (P = 0.1828);Loss of disorder (P = 0.1828);Loss of disorder (P = 0.1828);
MVP		1.0
MPC		0.44
ClinPred		0.78	D
GERP RS		4.7
Varity_R		0.77
gMVP		0.88

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: rs398122413; hg19: chr20-4680499;