rs74315406

Positions:

• chr20-4699870-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000311.5(PRNP):​c.650A>G​(p.Gln217Arg) variant causes a missense change. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.84

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000311.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 20-4699870-A-G is Pathogenic according to our data. Variant chr20-4699870-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699870-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRNP	NM_000311.5	c.650A>G	p.Gln217Arg	missense_variant	2/2	ENST00000379440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRNP	ENST00000379440.9	c.650A>G	p.Gln217Arg	missense_variant	2/2	1	NM_000311.5	P1
PRNP	ENST00000424424.2	c.650A>G	p.Gln217Arg	missense_variant	2/2	1		P1
PRNP	ENST00000430350.2	c.650A>G	p.Gln217Arg	missense_variant	2/2	1		P1
PRNP	ENST00000457586.2	c.650A>G	p.Gln217Arg	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Huntington disease-like 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 14, 2021

ClinVar contains an entry for this variant (Variation ID: 13402). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects PRNP function (PMID: 10079068, 10970892, 14761942, 19680558, 25959220, 26323476). 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. This missense change has been observed in individuals with Gerstmann-Sträussler-Scheinker syndrome (PMID: 1363810, 16025285). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with arginine at codon 217 of the PRNP protein (p.Gln217Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. -

PRNP-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 03, 2024

Variant summary: PRNP c.650A>G (p.Gln217Arg) results in a conservative amino acid change located in the Prion/Doppel protein, beta-ribbon domain (IPR022416) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251422 control chromosomes. c.650A>G has been reported in the literature in individuals affected with Gerstmann-Strvussler-Scheinker syndrome (Woulfe_2005, Hsiao_1992) and an internally identified individual with features of PRNP related disorders. These data indicate that the variant is likely to be associated with disease. Several publications reporting experimental evidence demonstrate that variant has an impact on protein stability and function (Apetri_2004, Jodoin_2009, Liemann_1999, Martinez_2015, Singh_2015) . The following publications have been ascertained in the context of this evaluation (PMID: 14761942, 1363810, 19680558, 10079068, 26323476, 25959220, 16025285). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Gerstmann-Straussler-Scheinker syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.8	M;M;.;.
MutationTaster	Benign	0.94	A;A
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.98	D;D;.;.
Vest4		0.87
MutPred		0.92		Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);
MVP		1.0
MPC		0.76
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.78
gMVP		0.98

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: rs74315406; hg19: chr20-4680516;