20-4699752-G-A

Variant names:

• chr20-4699752-G-A
• rs74315403
• NM_000311.5:c.532G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000311.5(PRNP):​c.532G>A​(p.Asp178Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 5.94

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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a strand (size 3) in uniprot entity PRIO_HUMAN there are 5 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, 0.968
• PP5: Variant 20-4699752-G-A is Pathogenic according to our data. Variant chr20-4699752-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699752-G-A is described in Lovd as [Pathogenic]. Variant chr20-4699752-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRNP	NM_000311.5	c.532G>A	p.Asp178Asn	missense_variant	Exon 2 of 2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9	c.532G>A	p.Asp178Asn	missense_variant	Exon 2 of 2	1	NM_000311.5	ENSP00000368752.4
PRNP	ENST00000424424.2	c.532G>A	p.Asp178Asn	missense_variant	Exon 2 of 2	1		ENSP00000411599.2
PRNP	ENST00000430350.2	c.532G>A	p.Asp178Asn	missense_variant	Exon 2 of 2	1		ENSP00000399376.2
PRNP	ENST00000457586.2	c.532G>A	p.Asp178Asn	missense_variant	Exon 2 of 2	1		ENSP00000415284.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000385 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRNP: PS3:Very Strong, PS4, PM2 -

Feb 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect by accelerated misfolding and forming oligomers faster than wild-type protein (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: 32775516, 19996123, 1671440, 25959220, 16313190, 19571725, 10588836, 20872767, 25281825, 18062918, 10079068, 24118545, 23723004, 25473397, 20096809, 17494694, 14761942, 23132868, 9813003, 21689662, 23430483, 20038778, 21552571, 19543376, 22912570, 23276223, 19565837, 20104755, 15623717, 27056979, 26791950, 26074146, 17013786, 29569252, 9855529, 9270595, 9531435, 19228673, 29718878, 16227536, 10050890, 24340298, 32946318, 1439789, 8105681, 30012679, 10787305, 15459517, 33726816, 28549449) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP4, PM2, PS4 -

Fatal familial insomnia Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Associated with Fatal Familial Insomnia phenotype; 1 of the 5 most common variants that account for 85% of genetic prion disease when in cis with Met129Val. -

-

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Gerstmann-Straussler-Scheinker syndrome;C1847650:Spongiform encephalopathy with neuropsychiatric features;C1864112:Huntington disease-like 1 Pathogenic:1

Feb 25, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 16313190, 23132868). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.73 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039359 /PMID: 1671440 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16227536, 26488179, 9270595, 9531435). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 10588836, 20038778). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Huntington disease-like 1 Pathogenic:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 178 of the PRNP protein (p.Asp178Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with genetic prion diseases (PMID: 1439789, 1671440, 9270595, 9531435, 10588836, 16227536, 17013786, 20038778, 26488179, 26791950). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39359). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRNP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRNP function (PMID: 9813003, 16313190, 17494694, 23132868, 27350609). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D;D;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.9	M;M;.;.
PhyloP100		5.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.91
MutPred		0.96		Gain of MoRF binding (P = 0.1052);Gain of MoRF binding (P = 0.1052);Gain of MoRF binding (P = 0.1052);Gain of MoRF binding (P = 0.1052);
MVP		1.0
MPC		1.4
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.72
gMVP		0.97
Mutation Taster		=6/94	disease causing (ClinVar)

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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Other links and lift over

dbSNP: rs74315403; hg19: chr20-4680398;