ClinVar Miner

Submissions for variant NM_000311.5(PRNP):c.538G>A (p.Val180Ile) (rs74315408)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000014344 SCV000267463 likely pathogenic Creutzfeldt-Jakob Disease, Familial 2016-03-18 criteria provided, single submitter reference population
Illumina Clinical Services Laboratory,Illumina RCV000020249 SCV000914280 pathogenic Genetic prion disease 2019-04-05 criteria provided, single submitter clinical testing The PRNP c.538G>A (p.Val180Ile) missense variant is the most common pathogenic variant found in association with Creutzfeldt-Jacob disease (CJD) (Lee et al. 2016). Across a selection of the available literature, the p.Val180Ile variant has been identified in a heterozygous state in at least 194 individuals with prion diseases and in one individual with CJD (Kitamoto et al. 1993; Chasseigneaux et al. 2006; Yang et al. 2010; Yoshida et al. 2010; Moe Lee et al. 2012; Higuma et al. 2013; Shi et al. 2014; Qina et al. 2014). Qina et al. (2014) also noted that only 11 out of 186 Japanese patients with the p.Val180Ile variant had a family history of dementia, suggesting that this variant may have reduced penetrance. Patients carrying the p.Val180Ile variant have a later onset of disease (late 70s), with a slower progression and a lower possibility of developing myoclonus, cerebellar, pyramidal signs and visual disturbance as compared to classic CJD presentation (Qina et al. 2014). The p.Val180Ile variant was absent from 159 control individuals without neurological diseases from the above studies but is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. This frequency is unexpectedly high given the expected prevalence of this condition. Due to the large number of clinical cases with genetic prion diseases carrying this variant, this variant is classified as pathogenic for genetic prion diseases. However, the specific implications of this variant are somewhat uncertain given the later onset, milder presentation, and high population frequency that have been associated with this variant. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001212635 SCV001384224 pathogenic Huntington disease-like 1 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 180 of the PRNP protein (p.Val180Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs74315408, ExAC 0.03%). This variant has been observed in several individuals with clinical features of Creutzfeldt-Jakob syndrome or prion disease (PMID: 8461023, 22999564, 25482600, 21269331, 23555862). A large case control study reported that individuals carrying this variant have a life-time risk of developing prion disease of approximately 1% (PMID: 26791950). ClinVar contains an entry for this variant (Variation ID: 13405). This variant has been reported to affect PRNP protein function (PMID: 17494694, 23132868, 23527023, 29382530). In summary, this variant is reported to cause prion 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).
OMIM RCV000014344 SCV000034593 pathogenic Creutzfeldt-Jakob Disease, Familial 2004-02-10 no assertion criteria provided literature only
GeneReviews RCV000014344 SCV000040603 pathogenic Creutzfeldt-Jakob Disease, Familial 2020-12-29 no assertion criteria provided literature only One of the five most common variants that account for 85% of genetic prion disease.

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