rs74315407

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PM1PP5_Very_StrongBS2

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 Likely pathogenic,low penetrance (★★).

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

Publications

154 publications found

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 Gene-Disease associations (from GenCC):

Gerstmann-Straussler-Scheinker syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
Huntington disease-like 1
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
inherited Creutzfeldt-Jakob disease
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
familial Alzheimer-like prion disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
fatal familial insomnia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
PrP systemic amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRNP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000311.5

PP5

Variant 20-4699848-G-A is Pathogenic according to our data. Variant chr20-4699848-G-A is described in ClinVar as Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance. ClinVar VariationId is 13403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRNP	NM_000311.5 link	c.628G>A	p.Val210Ile	missense_variant	Exon 2 of 2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PRNP	ENST00000379440.9 link	c.628G>A	p.Val210Ile	missense_variant	Exon 2 of 2	1	NM_000311.5	ENSP00000368752.4
PRNP	ENST00000424424.2 link	c.628G>A	p.Val210Ile	missense_variant	Exon 2 of 2	1		ENSP00000411599.2
PRNP	ENST00000430350.2 link	c.628G>A	p.Val210Ile	missense_variant	Exon 2 of 2	1		ENSP00000399376.2
PRNP	ENST00000457586.2 link	c.628G>A	p.Val210Ile	missense_variant	Exon 2 of 2	1		ENSP00000415284.2

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

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251460

AF XY:

0.0000147

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 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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151818

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41314

American (AMR)

AF:

0.00

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Associated with genetic Creutzfeldt-Jakob disease phenotype. One of the five most common variants that account for 85% of genetic prion disease. -

Oct 15, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Pathogenic:1

Jan 29, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Huntington disease-like 1

Pathogenic:1

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic, low penetrance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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;.;.

PhyloP100

2.1

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

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over