Submissions for variant NM_000311.5(PRNP):c.628G>A (p.Val210Ile)

gnomAD frequency: 0.00002  dbSNP: rs74315407

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532969	SCV000644931	pathogenic, low penetrance	Huntington disease-like 1	2023-10-03	criteria provided, single submitter	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–mouse 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).
Fulgent Genetics, Fulgent Genetics	RCV002476962	SCV002794569	likely pathogenic	Inherited Creutzfeldt-Jakob disease; Gerstmann-Straussler-Scheinker syndrome; Fatal familial insomnia; Huntington disease-like 1; Kuru, susceptibility to; Spongiform encephalopathy with neuropsychiatric features	2021-10-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018625	SCV005011763	pathogenic	Inborn genetic diseases	2024-01-29	criteria provided, single submitter	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.
OMIM	RCV000014342	SCV000034591	pathogenic	Inherited Creutzfeldt-Jakob disease	1999-10-15	no assertion criteria provided	literature only
GeneReviews	RCV000014342	SCV000040609	not provided	Inherited Creutzfeldt-Jakob disease		no assertion provided	literature only	Associated with genetic Creutzfeldt-Jakob disease phenotype. One of the five most common variants that account for 85% of genetic prion disease.