NM_004562.2(PRKN):c.758G>A (p.Cys253Tyr) is a missense variant in the parkin gene, which is associated with autosomal recessive early-onset Parkinson disease.1 The variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency is 0.00159% (4/251,238 alleles, 0 homozygotes), and gnomAD v4.1 allele frequency is 0.00068% (11/1,614,112 alleles, 0 homozygotes). This satisfies PM2 at moderate strength.2 p.Cys253Tyr lies within the linker region (residues 204–293) of parkin, a critical functional domain essential for interaction with C2 domain-containing proteins such as synaptotagmin XI. Sironi et al. (2008) characterized this domain as functionally critical. This satisfies PM1 at moderate strength.3 The variant has been observed in multiple unrelated patients with Parkinson disease. Sun et al. (2006) identified c.758G>A (p.Cys253Tyr) as a compound heterozygous mutation with Ex2-4del in two affected siblings from the GenePD study. Sironi et al. (2008) identified the variant in a homozygous state in one unrelated early-onset PD patient from an Italian cohort. This satisfies PS4 at supporting strength.4 Co-segregation with disease was observed in one family: Sun et al. (2006) reported Family 3 in which both affected siblings (onset ages 28 and 37) were compound heterozygous for c.758G>A and Ex2-4del. This satisfies PP1 at supporting strength.5 The REVEL in silico predictor returns a score of 0.818, which is above the threshold for deleterious prediction. BayesDel (0.395) and SpliceAI (max delta 0.00) do not support a deleterious effect. Given the conflicting predictions, PP3 is applied at supporting strength.6 PVS1 is not applicable as the variant is a missense substitution, not a null variant. PS1, PS2, PS3, PS5, PM5, PM6, PP2, PP4, PP5, BA1, BS1, BS2, BS3, BS4, BP1, BP2, BP4, BP5, BP6, and BP7 are not met or not applicable based on available evidence.7 Applying generic ACMG/AMP 2015 classification rules: two moderate criteria (PM1, PM2) plus three supporting criteria (PS4, PP1, PP3) satisfy the Likely Pathogenic classification threshold (2 moderate + ≥2 supporting). No benign criteria are met.8
PRKN
Final classification
Likely Pathogenic
PRKN c.758G>A · p.Cys253Tyr
PRKN
NM_004562.2(PRKN):c.758G>A (p.Cys253Tyr) is a missense variant in the parkin gene, which is associated with autosomal recessive early-onset Parkinson disease.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS4 supporting, PM1 moderate, PM2 moderate, PP1 supporting, PP3 supporting; combination = 2 moderate + 3 supporting, which maps to Likely Pathogenic.
Classification rationale
PS4PM1PM2PP1PP3
Likely Pathogenic
PRKN c.758G>A
PS4 + PM1 + PM2 + PP1 + PP3
→
Likely Pathogenic
1
PMID:16769863 ↗PMID:18519021 ↗pvs1_gene_context
6
revelbayesdelspliceai ↗
8
generic_acmg_combination_rulesPMID:25741868 ↗
Gene diagram
· NM_004562.2 · variants mapped to exon structure
PRKN
NM_004562.2
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 18 assessed
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
✓
PS4
supporting
Pathogenic
PS4 is met at supporting strength: p.Cys253Tyr has been observed in multiple unrelated patients with Parkinson disease across at least two independent publications. Sun et al. (2006) identified c.758G>A (p.Cys253Tyr) as a compound heterozygous mutation (with Ex2-4del) in two affected siblings (Family 3, onset ages 28 and 37). Sironi et al. (2008) identified p.C253Y in a homozygous state in one unrelated early-onset PD patient from an Italian cohort. Four clinical laboratories have submitted this variant as Pathogenic and one as Likely Pathogenic in ClinVar. Although no formal case-control OR is available, the observation across multiple independent cohorts supports PS4 at supporting level.
Observed in two independent PD patient cohorts (Sun 2006 GenePD study: compound heterozygous in Family 3Sironi 2008 Italian cohort: homozygous in one EOPD patient). ClinVar: 4 labs classify as Pathogenic1 as Likely Pathogenic (ClinVar ID 645725).
✓
PM1
moderate
Pathogenic
PM1 is met at moderate strength: p.Cys253Tyr is located in the linker region (residues 204-293) of parkin, a critical functional domain that connects the ubiquitin-like domain to the RING finger motifs. Sironi et al. (2008) characterize this region as essential for parkin interaction with C2 domain-containing proteins such as synaptotagmin XI. The variant substitutes a cysteine at position 253 with tyrosine, potentially disrupting structurally important residue interactions within this well-characterized functional domain. While the exact residue is not a statistical hotspot at cancerhotspots.org, domain-level PM1 is warranted given the functional characterization.
Sironi 2008 describes linker region (p.204-293) as essential for interaction with C2 domain-containing proteins. p.Cys253Tyr lies within this domain. Hotspots analysis: not a statistically significant residue-level hotspotbut domain-level PM1 applies per the well-characterized functional domain rule.
✓
PM2
moderate
Pathogenic
PM2 is met at moderate strength: the variant is present at extremely low frequency in population databases. gnomAD v2.1 reports an allele frequency of 0.00159% (4/251,238 alleles, 0 homozygotes), and gnomAD v4.1 reports an allele frequency of 0.00068% (11/1,614,112 alleles, 0 homozygotes). Both are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada v1.0. Highest subpopulation frequency is 0.00289% (Admixed American, v2.1), also below threshold.
gnomAD v2.1: AF=1.59e-5 (4/2512380 hom)
✓
PP1
supporting
Pathogenic
PP1 is met at supporting strength: Sun et al. (2006) report co-segregation of c.758G>A (p.Cys253Tyr) with Parkinson disease in Family 3. The variant was found in compound heterozygous state (with Ex2-4del) in two affected siblings with onset ages of 28 and 37 years. The Labcorp/Invitae ClinVar submission (SCV000939555) also notes segregation with disease in related individuals, though specific details are not provided.
Sun 2006 Family 3: c.758G>A (p.Cys253Tyr) compound heterozygous with Ex2-4del in 2 affected siblings (onset 2837). Labcorp ClinVar submission notes segregation with disease in related individuals.
✓
PP3
supporting
Pathogenic
PP3 is met at supporting strength: the REVEL in silico predictor returns a score of 0.818, which is above commonly used thresholds for deleterious prediction (typically >0.5 or >0.75). However, BayesDel returns 0.395 (below the typical 0.5 threshold), and SpliceAI predicts no splicing impact (max delta = 0.00). The conflicting in silico evidence supports PP3 at supporting level only.
REVEL score: 0.818 (deleterious prediction). BayesDel score: 0.395 (below typical 0.5 threshold). SpliceAI max delta: 0.00 (no splicing impact predicted). Only one of three computational tools supports a deleterious effect.
Assessed · not applied
Pathogenic
PS1
PS1 is not met: no evidence of a different nucleotide change at the same codon producing the same amino acid change (p.Cys253Tyr) that has been previously classified as pathogenic.
PS2
PS2 is not met: no de novo observation data (with confirmed paternity and maternity) is available in the case materials for this variant.
PS3
PS3 is not met: no experimental functional data exists for p.Cys253Tyr specifically or for a systematically characterized range that includes residue 253.
PM5
PM5 is not met: no pathogenic missense variant at the same amino acid residue (Cys253) with a different amino acid change has been identified in ClinVar or the case literature.
PM6
PM6 is not met: no confirmed de novo observation data is available.
PP2
PP2 is not met: insufficient data is available on the missense constraint (Z-score) for PRKN to determine whether the gene has a low rate of benign missense variation.
PP4
PP4 is not assessed: no specific patient phenotype data (beyond diagnosis of Parkinson disease) is available in the case materials to evaluate whether the patient's phenotype or family history is highly specific for PRKN-related disease.
PP5
PP5 is not met: while ClinVar reports this variant as Pathogenic (4 clinical laboratories) and Likely Pathogenic (1 clinical laboratory), the ClinVar review status is 'criteria provided, single submitter' (1-star).
Benign
BA1
BA1 is not met: the variant allele frequency in gnomAD (v2.1: 0.00159%; v4.1: 0.00068%) is far below the 1% threshold required for BA1.
BS1
BS1 is not met: the variant allele frequency in gnomAD (v2.1: 0.00159%; v4.1: 0.00068%) is far below the 0.3% threshold for BS1.
BS2
BS2 is not met: no homozygous observation of this variant has been reported in healthy adult controls.
BS3
BS3 is not met: no experimental functional studies demonstrating no deleterious effect of p.Cys253Tyr on parkin protein function have been identified.
BS4
BS4 is not met: no evidence of lack of segregation with disease is available.
BP1
BP1 is not met: PRKN does not have a disease mechanism limited primarily to truncating variants.
BP2
BP2 is not met: no observation of this variant in trans with a known pathogenic variant in a healthy individual has been reported.
BP4
BP4 is not met: the in silico evidence is conflicting rather than uniformly benign.
BP5
BP5 is not met: there is no strong benign assertion for this variant in ClinVar.
BP6
BP6 is not met: identical to the PP5 logic, the ClinVar review status for this variant is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold required for BP6.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.81489e-06; MAF= 0.00068%, 11/1614112 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66594e-05; MAF= 0.00167%, 1/60026 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.59212e-05; MAF= 0.00159%, 4/251238 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89302e-05; MAF= 0.00289%, 1/34566 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00068%
· 11 / 1,614,112
0 hom · FAF 0.00043%
0 hom · FAF 0.00043%
Admixed American 1 / 60,026 |
0.0017% |
European (non-Finnish) 10 / 1,179,982 |
0.00085% |
+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0016%
· 4 / 251,238
0 hom · FAF 0.0007%
0 hom · FAF 0.0007%
Admixed American 1 / 34,566 |
0.0029% |
European (non-Finnish) 3 / 113,604 |
0.0026% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 645725)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.818. BayesDel score = 0.395385.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PRKN encodes a tumor suppressor invovled in tagging cellular proteins for degradation. PRKN is inactivated in various cancer types, and its dysfunctio
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.
Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study.
Searched
c.758G>ACys253TyrC253Yp.Cys253Tyr
Found
c.758G>A (p.Cys253Tyr) identified as a compound heterozygous mutation with Ex2-4del in Family 3 of the GenePD study. Two affected siblings carried both mutations with onset ages of 28 and 37 years. The variant was detected among 23 mutation-positive families (12.6%) in a cohort of 183 familial PD families.
Variant
✓ Names this variant — characterised directly
Applied to
→PP1 supports · met
→PS4 supports · met
Why
Variant-specific observation in familial PD confirmed. Used to support PS4 (multiple unrelated patients) and PP1 (co-segregation in Family 3).
c.758G>A ... p.Cys253Tyr ... Compound Het ... Ex2-4del
Location Table 1 (Family 3, line 390-393); Figure 1 (line 589); Results, paragraph 1 · full text
Parkin analysis in early onset Parkinson's disease.
Searched
c.758G>ACys253TyrC253Yp.C253Yc.G859Ac.859G>A
Found
p.C253Y (listed as c.G859A under NM_004562 numbering) was identified in a homozygous state in one patient among 146 consecutively enrolled early-onset PD patients from an Italian center. The variant was among seven previously reported pathogenic point mutations. Overall, 12 of 146 patients (8.2%) had homozygous or compound heterozygous parkin mutations. The linker region (residues 204-293), where p.C253Y resides, was characterized as essential for interaction with C2 domain-containing proteins such as synaptotagmin XI.
Variant
✓ Names this variant — characterised directly
Applied to
→PM1 supports · met
→PS4 supports · met
Why
Variant-specific observation confirmed in an independent Italian EOPD cohort. Used to support PS4 (second independent cohort) and PM1 (linker domain characterization).
seven of these have been previously reported and are known as pathogenic changes (p.R42P, p.M192L, p.T240M, p.C253Y, p.R275W, p.E409X, p.R402C)
Location Table 1 (lines 281-285); Results section 3.1 (line 182) · full text
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
23279440 ↗
EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson's disease.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
29398453 ↗
Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
CLINVAR
24493721 ↗
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
CLINVAR
22964825 ↗
Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement.
CLINVAR