rs74315407
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP5_Strong
The NM_000311.5(PRNP):c.628G>A(p.Val210Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V210F) has been classified as Pathogenic.
Frequency
Consequence
NM_000311.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRNP | NM_000311.5 | c.628G>A | p.Val210Ile | missense_variant | 2/2 | ENST00000379440.9 | NP_000302.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRNP | ENST00000379440.9 | c.628G>A | p.Val210Ile | missense_variant | 2/2 | 1 | NM_000311.5 | ENSP00000368752.4 | ||
PRNP | ENST00000424424.2 | c.628G>A | p.Val210Ile | missense_variant | 2/2 | 1 | ENSP00000411599.2 | |||
PRNP | ENST00000430350.2 | c.628G>A | p.Val210Ile | missense_variant | 2/2 | 1 | ENSP00000399376.2 | |||
PRNP | ENST00000457586.2 | c.628G>A | p.Val210Ile | missense_variant | 2/2 | 1 | ENSP00000415284.2 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151818Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251460Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135906
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727248
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151818Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74126
ClinVar
Submissions by phenotype
Inherited Creutzfeldt-Jakob disease Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 15, 1999 | - - |
not provided, no classification provided | literature only | GeneReviews | - | Associated with genetic Creutzfeldt-Jakob disease phenotype. One of the five most common variants that account for 85% of genetic prion disease. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 29, 2024 | 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. - |
Gerstmann-Straussler-Scheinker syndrome;C0206042:Fatal familial insomnia;C0751254:Inherited Creutzfeldt-Jakob disease;C1847650:Spongiform encephalopathy with neuropsychiatric features;C1855588:Kuru, susceptibility to;C1864112:Huntington disease-like 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 26, 2021 | - - |
Huntington disease-like 1 Pathogenic:1
Pathogenic, low penetrance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2023 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at