NM_004562.2(PRKN):c.758G>A

PRKN · NP_004553.2:p.(Cys253Tyr) · NM_004562.2

GRCh37: chr6:162206917 C>T · GRCh38: chr6:161785885 C>T

Gene: PRKN Transcript: NM_004562.2

Final call

Likely Pathogenic

PS4 supporting PM1 moderate PM2 moderate PP1 supporting PP3 supporting

Variant details

Gene

PRKN

Transcript

NM_004562.2

Protein

NP_004553.2:p.(Cys253Tyr)

gnomAD AF

6.814892646854741e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

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.

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is not applicable: NM_004562.2(PRKN):c.758G>A is a missense variant (p.Cys253Tyr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 decision framework confirms the variant falls into the 'other' bucket and does not trigger PVS1.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	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. The PM5 candidate search was unable to identify same-residue comparator variants.	pm5_candidates
PS2	Not met	PS2 is not met: no de novo observation data (with confirmed paternity and maternity) is available in the case materials for this variant.
PS3	Not met	PS3 is not met: no experimental functional data exists for p.Cys253Tyr specifically or for a systematically characterized range that includes residue 253. The literature reviewed (Sun 2006, Sironi 2008) reports the variant in patient cohorts but does not present functional assay data for this variant. OncoKB confirms no curated variant-specific functional evidence.	oncokb
PS4	Met	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.	PMID:16769863 PMID:18519021 clinvar
PS5	Not met	PS5 is not met: no de novo observation data (with confirmed paternity and maternity) is available in the case materials. This criterion requires a confirmed de novo occurrence and is distinct from PS2 which also requires parental confirmation.
PM1	Met	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.	PMID:18519021
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	Not met	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. The automated PM5 candidate search found no same-residue comparator variants.	pm5_candidates
PM6	Not met	PM6 is not met: no confirmed de novo observation data is available. The ClinVar submissions are all classified as germline/inherited origin. No de novo reports for this variant were identified in the reviewed literature.	clinvar
PP1	Met	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.	PMID:16769863 clinvar
PP2	Not met	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. PRKN is an autosomal recessive gene with both missense and loss-of-function pathogenic mechanisms, making PP2 application uncertain without constraint metrics.
PP3	Met	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 bayesdel spliceai
PP4	Not assessed	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. While early-onset Parkinson disease is consistent with PRKN-related disease, detailed clinical data (age of onset, family history, specific features) for the proband were not provided in the case summary.
PP5	Not met	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). PP5 requires a 3-star expert panel review status to be applied. The 1-star review status does not meet this threshold, regardless of the number of concordant clinical laboratory submissions.	clinvar
BA1	Not met	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. This variant is extremely rare in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	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. This variant is too rare in population databases to support a benign interpretation.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 is not met: no homozygous observation of this variant has been reported in healthy adult controls. The variant is observed in gnomAD with 0 homozygotes across both v2.1 and v4.1 datasets.	gnomad_v2 gnomad_v4
BS3	Not met	BS3 is not met: no experimental functional studies demonstrating no deleterious effect of p.Cys253Tyr on parkin protein function have been identified. The reviewed literature does not contain functional assays for this variant showing intact protein function.
BS4	Not met	BS4 is not met: no evidence of lack of segregation with disease is available. The available segregation data (Sun 2006, Family 3) actually shows co-segregation of the variant with disease in two affected siblings.	PMID:16769863
BP1	Not met	BP1 is not met: PRKN does not have a disease mechanism limited primarily to truncating variants. Both missense and truncating variants are well-established causes of autosomal recessive Parkinson disease, with missense variants accounting for a substantial fraction of reported pathogenic variants (e.g., p.R275W, p.R42P, p.T240M, p.C253Y).	PMID:18519021 PMID:16769863
BP2	Not met	BP2 is not met: no observation of this variant in trans with a known pathogenic variant in a healthy individual has been reported. The variant has been observed in trans with Ex2-4del (Sun 2006, Family 3) in affected individuals, which is consistent with pathogenicity, not benignity.	PMID:16769863
BP4	Not met	BP4 is not met: the in silico evidence is conflicting rather than uniformly benign. REVEL returns a score of 0.818, which strongly predicts a deleterious effect. While BayesDel (0.395) is below the typical pathogenicity threshold and SpliceAI (0.00) predicts no splicing impact, the strong REVEL prediction precludes a BP4 determination. BP4 requires multiple lines of computational evidence suggesting no impact.	revel bayesdel spliceai
BP5	Not met	BP5 is not met: there is no strong benign assertion for this variant in ClinVar. The variant is classified as Pathogenic or Likely Pathogenic by all submitting laboratories. No alternative source provides a benign classification.	clinvar
BP6	Not met	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. Furthermore, all ClinVar submissions classify this variant as Pathogenic or Likely Pathogenic, making BP6 inapplicable.	clinvar
BP7	N/A	BP7 is not applicable: c.758G>A is a missense variant (p.Cys253Tyr), not a synonymous (silent) variant. BP7 applies exclusively to synonymous variants for which splicing algorithms predict no impact and the nucleotide is not highly conserved.
BP3	N/A	BP3 is not applicable: the variant is a substitution (missense), not an in-frame deletion/insertion in a repetitive region.
PM3	N/A	PM3 is not applicable: no data on biallelic (trans) observation with a pathogenic variant is available in the case materials beyond the compound heterozygous observation in Sun 2006 Family 3, which was noted but PM3 was skipped per the assessment list.
PM4	N/A	PM4 is not applicable: the variant is a missense substitution (p.Cys253Tyr), not a protein-length altering change (in-frame deletion/insertion, stop-loss, or initiation codon variant).

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