Submissions for variant NM_000311.5(PRNP):c.623G>A (p.Arg208His)

gnomAD frequency: 0.00004  dbSNP: rs74315412

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001823096	SCV002072689	likely pathogenic	not provided	2023-03-14	criteria provided, single submitter	clinical testing	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)
Invitae	RCV001851853	SCV002294354	pathogenic	Huntington disease-like 1	2023-08-17	criteria provided, single submitter	clinical testing	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002468968	SCV002766014	likely pathogenic	PRNP-Related Disorders	2022-11-03	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000014352	SCV000034601	uncertain significance	Inherited Creutzfeldt-Jakob disease	2006-03-01	no assertion criteria provided	literature only