rs74315412

Positions:

chr20-4699843-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong

The NM_000311.5(PRNP):c.623G>A(p.Arg208His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PRNP
NM_000311.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 2.38

Variant links:

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]

PRNP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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

PP5

Variant 20-4699843-G-A is Pathogenic according to our data. Variant chr20-4699843-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5 linkuse as main transcript	c.623G>A	p.Arg208His	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 linkuse as main transcript	c.623G>A	p.Arg208His	missense_variant	2/2	1	NM_000311.5	ENSP00000368752	P1	P04156-1
PRNP	ENST00000424424.2 linkuse as main transcript	c.623G>A	p.Arg208His	missense_variant	2/2	1		ENSP00000411599	P1	P04156-1
PRNP	ENST00000430350.2 linkuse as main transcript	c.623G>A	p.Arg208His	missense_variant	2/2	1		ENSP00000399376	P1	P04156-1
PRNP	ENST00000457586.2 linkuse as main transcript	c.623G>A	p.Arg208His	missense_variant	2/2	1		ENSP00000415284	P1	P04156-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251464

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151830

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000594

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; As the variant is also observed in control populations, it may be associated with reduced penetrance or may slightly increase prion disease risk (Minikel et la., 2016); This variant is associated with the following publications: (PMID: 21689662, 25450391, 25959220, 30898147, 15739100, 16533975, 10079068, 17494694, 14761942, 20541558, 22488860, 15753435, 21552571, 21791975, 20301407, 8909447, 23979103, 20855418, 26488179, 26791950, 32458274, 33917419, 34199205, 34487324, 34296847, 35888666, 36614069, 36285115, 35294674, 35813946, 35288744) -

Huntington disease-like 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PRNP function (PMID: 10079068, 14761942, 17494694, 20541558, 25959220). 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. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 208 of the PRNP protein (p.Arg208His). This variant is present in population databases (rs74315412, gnomAD 0.03%). This missense change has been observed in individuals with genetic prion disease (PMID: 2458274, 8909447, 15739100, 15753435, 16533975). This variant is also known as R207H. ClinVar contains an entry for this variant (Variation ID: 13411). -

PRNP-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 03, 2022

Variant summary: PRNP c.623G>A (p.Arg208His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251464 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PRNP causing PRNP-Related Disorders (6e-05 vs ND), allowing no conclusion about variant significance. c.623G>A has been reported in the literature in individuals affected with PRNP related disorders such as Creutzfeldt-Jakob Disease confirmed in many cases by autopsy and histological findings (example: Basset-Leobon_2006, Caperllari_2005_Chen_2011 and Roeber_2005 etc.). These data indicate that the variant is likely to be associated with disease. It has also been reported in unaffected individuals (Chen_2011) as well as in patients with no family history, however, a low penetrance has been sugguested for this variant (example: Caperllari_2005). Several publications reports experimental evidence suggest that this variant affects PRNP protein function (example: Apetri_2004, Cardone_2014, Gerum_2010 and Liemann_1999) supporting a pathogenic role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inherited Creutzfeldt-Jakob disease

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Mar 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

T;T;T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Benign

0.74

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.47

T;T;T;T

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.7

M;M;.;.

MutationTaster

Benign

0.99

A;A

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.86

N;N;N;N

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.99

D;D;.;.

Vest4

0.75

MVP

1.0

MPC

1.4

ClinPred

0.27

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.67

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over