rs74315407

Positions:

chr20-4699848-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP5_Strong

The NM_000311.5(PRNP):c.628G>A(p.Val210Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V210F) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PRNP
NM_000311.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic/Pathogenic, low penetrance criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 2.10

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 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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-4699848-G-T is described in Lovd as [Pathogenic].

PP5

Variant 20-4699848-G-A is Pathogenic according to our data. Variant chr20-4699848-G-A is described in ClinVar as [other]. Clinvar id is 13403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic_low_penetrance=1, not_provided=1, Pathogenic=1, Likely_pathogenic=1}. Variant chr20-4699848-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5 linkuse as main transcript	c.628G>A	p.Val210Ile	missense_variant	2/2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PRNP	ENST00000379440.9 linkuse as main transcript	c.628G>A	p.Val210Ile	missense_variant	2/2	1	NM_000311.5	ENSP00000368752.4	P04156-1
PRNP	ENST00000424424.2 linkuse as main transcript	c.628G>A	p.Val210Ile	missense_variant	2/2	1		ENSP00000411599.2	P04156-1A2A2V1
PRNP	ENST00000430350.2 linkuse as main transcript	c.628G>A	p.Val210Ile	missense_variant	2/2	1		ENSP00000399376.2	P04156-1
PRNP	ENST00000457586.2 linkuse as main transcript	c.628G>A	p.Val210Ile	missense_variant	2/2	1		ENSP00000415284.2	P04156-1X6RKS3

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251460

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727248

show subpopulations

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:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151818

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74126

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inherited Creutzfeldt-Jakob disease

Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 1999	- -
not provided, no classification provided	literature only	GeneReviews	-	Associated with genetic Creutzfeldt-Jakob disease phenotype. One of the five most common variants that account for 85% of genetic prion disease. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.628G>A (p.V210I) alteration is located in exon 2 (coding exon 1) of the PRNP gene. This alteration results from a G to A substitution at nucleotide position 628, causing the valine (V) at amino acid position 210 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/251460) total alleles studied. The highest observed frequency was 0.002% (2/113744) of European (non-Finnish) alleles. This variant was reported in multiple individuals who met clinical criteria for genetic prion disease (Mastrianni, 2001; Renard, 2018; Xiao, 2020), and multiple individuals with features consistent with genetic prion disease (Pocchiari, 1993; Mouillet-Richard, 1999; Furukawa, 1996; Mastrianni, 2001; Tajima, 2014; Conte, 2015; Imbriani, 2016; Xiao, 2020). This variant was also reported in unaffected family members suggesting reduced penetrance (Pocchiari, 1993; Mouillet-Richard, 1999). This amino acid position is well conserved in available vertebrate species. Based on internal structural analysis, p.V210I is moderately destabilizing to the local structure (van der Kamp, 2010; Jodoin, 2007). In multiple assays testing PRNP function, this variant showed functionally abnormal results (Peters, 2016; Jodoin, 2007). Based on the available evidence, this alteration is classified as pathogenic. -

Gerstmann-Straussler-Scheinker syndrome;C0206042:Fatal familial insomnia;C0751254:Inherited Creutzfeldt-Jakob disease;C1847650:Spongiform encephalopathy with neuropsychiatric features;C1855588:Kuru, susceptibility to;C1864112:Huntington disease-like 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 26, 2021

- -

Huntington disease-like 1

Pathogenic:1

Pathogenic, low penetrance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 210 of the PRNP protein (p.Val210Ile). This variant is present in population databases (rs74315407, gnomAD 0.002%). This variant has been reported in many cases of sporadic and familial Creutzfeldt-Jakob disease (CJD) (PMID: 26268049, 26578040, 24583440, 10526198, 7902693). In several cases, this variant has also been identified in unaffected family members, indicating that it is an incompletely penetrant allele (PMID: 26791950, 10526198, 7902693). A large case control study confirmed this finding, and reported that individuals carrying this variant have a life-time risk of developing prion disease of approximately 10% (PMID: 26791950). ClinVar contains an entry for this variant (Variation ID: 13403). 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. Experimental studies have shown that this missense change leads to functional and structural changes in the PRNP protein (PMID: 21839748, 21909425, 22947063, 10079068, 14761942). In addition, mice with a chimeric human‚Äìmouse PRNP transgene that were inoculated with brain extract from affected individuals carrying this variant developed prion disease (PMID: 11756597). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the PRNP gene, it has been classified as Pathogenic (low penetrance). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;T;T;.

Eigen

Benign

0.0035

Eigen_PC

Benign

0.084

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.93

.;D;D;D

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.51

D;D;D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Benign

1.5

L;L;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

0.080

N;N;N;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Benign

0.77

T;T;T;T

Polyphen

0.21

B;B;.;.

Vest4

0.68

MVP

1.0

MPC

0.63

ClinPred

0.30

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.78

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