Variant classification summary

NM_004562.2: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

PM1 moderate PM2 supporting PM3 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

1

PM1 (Moderate): missense change within the RING1 zinc-binding domain of parkin, a critical functional region containing a cluster of established pathogenic missense variants and no documented benign variation at the residue.

2

PM3 (Moderate): the variant is homozygous in an affected early-onset Parkinson disease proband, consistent with the autosomal recessive inheritance of PRKN-related parkinsonism.

3

PM2 (Supporting): extremely rare in population databases, with gnomAD allele frequencies near 0.001% and zero homozygotes.

4

PP1 (Supporting): co-segregates with disease in two affected family members carrying the variant in trans with a pathogenic exon 2-4 deletion.

5

PP3 (Supporting): two independent in silico predictors (REVEL 0.818, BayesDel 0.395) support a deleterious effect, with no predicted splice impact.

6

Overall: PM1 and PM3 at Moderate combined with PM2, PP1, and PP3 at Supporting satisfies the '2 Moderate + 2 Supporting' rule, yielding a final classification of Likely Pathogenic.

Final determination: 2 Moderate (PM1, PM3) + 2 Supporting (PP1, PP3) → Likely Pathogenic per generic ACMG/AMP 2015; PM2 supporting additional; no strong/very-strong criterion present

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 does not apply: this is a missense change (p.Cys253Tyr), not a null variant class such as nonsense, frameshift, or canonical splice-site disruption that would trigger nonsense-mediated decay or otherwise abolish protein function.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	PS1 could not be assessed: no different nucleotide change at position c.758 producing the same p.Cys253Tyr amino acid change was found in any source, so there is no documented alternate-nucleotide variant established as pathogenic.	clinvar PMID:16769863 PMID:18519021 PMID:25741868
PS2	Not met	Not met: no de novo occurrence of c.758G>A is documented. All ClinVar submissions record germline origin and one explicitly records inheritance (Solve-RD), and no parental testing or de novo event appears in the reviewed literature; de novo origin is also not the expected mechanism for this autosomal recessive disorder.	clinvar PMID:25741868
PS3	Not assessed	PS3 could not be assessed: no variant-specific functional assay for p.Cys253Tyr exists in the reviewed literature. The reported cases are clinical observations (homozygous and compound-heterozygous patients) without functional testing, and in silico predictions such as REVEL and BayesDel do not qualify as functional studies under ACMG/AMP 2015.	PMID:25741868 PMID:18519021 PMID:16769863 oncokb
PS4	Not met	Not met: no case-control study shows enrichment of this variant in affected individuals. The evidence consists only of case reports and family-based observations in which the variant was not compared against controls, and its population frequency is extremely low.	PMID:18519021 PMID:16769863 clinvar gnomad_v2 gnomad_v4
PM1	Met	PM1 (Moderate): p.Cys253Tyr lies in exon 7 within the RING1 zinc-binding domain of parkin, the critical region for the protein's E3 ubiquitin ligase activity. Multiple independent pathogenic missense variants cluster in this domain (e.g., p.Cys238Trp, p.Thr240Met, p.Arg275Trp), and no benign variation is documented at residue 253.	PMID:18519021 PMID:16769863 gnomad_v2 gnomad_v4 PMID:25741868
PM2	Met	PM2 (Supporting): the variant is extremely rare in population databases, with gnomAD allele frequencies of 0.0016% (v2.1) and 0.0007% (v4.1) and zero homozygotes, far below the 0.1% threshold. It is absent from gnomAD-Canada, and the single elevated subpopulation frequency (Bulgarian, v2.1) is a small-sample artifact not seen in v4.1.	gnomad_v2 gnomad_v4 gnomad_canada PMID:18519021 PMID:16769863
PM3	Met	PM3 (Moderate): PRKN-related parkinsonism is autosomal recessive, and the variant is documented homozygous (in trans with itself) in an affected early-onset Parkinson disease proband with onset at age 20. A single affected homozygous proband supports moderate strength; additional in-trans observations would be needed to upgrade.	PMID:18519021 clinvar
PM4	N/A	PM4 does not apply: the variant is a missense substitution, not an in-frame insertion/deletion or stop-loss change, so protein length is unchanged.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: p.Cys253Tyr is itself the established pathogenic change at this residue, so the novel-missense prerequisite fails, and no different pathogenic missense at residue 253 (e.g., p.Cys253Phe or p.Cys253Trp) is documented in any source.	pm5_candidates clinvar PMID:18519021 PMID:16769863
PM6	Not met	Not met: no source reports the variant as de novo, whether assumed or confirmed. The only explicit inheritance annotation is inherited (Solve-RD), no parental genotype data are available, and de novo origin is not the expected mechanism for this autosomal recessive disorder.	clinvar PMID:25741868
PP1	Met	PP1 (Supporting): the variant co-segregates with disease, with two affected family members in a GenePD family (onset ages 28 and 37) both carrying c.758G>A in trans with a large pathogenic exon 2-4 deletion. Two affected individuals in one family support supporting strength.	PMID:16769863 clinvar
PP2	Not assessed	PP2 could not be fully assessed: missense variants are an established disease mechanism in PRKN, but no gene-level missense constraint data (e.g., a gnomAD missense Z-score) were available to evaluate the gene's rate of benign missense variation.	PMID:18519021 PMID:16769863 pvs1_gene_context
PP3	Met	PP3 (Supporting): two independent calibrated missense predictors support a deleterious effect, with REVEL 0.818 and BayesDel 0.395 both above the SVI-calibrated supporting thresholds. SpliceAI predicts no splice impact (score 0.00), consistent with a protein-level effect.	revel bayesdel spliceai PMID:25741868 generic_acmg_combination_rules
PP4	Not assessed	PP4 could not be assessed: no proband-level clinical phenotype data (onset age, family history, inheritance pattern) were available to evaluate whether the phenotype is highly specific for PRKN-related disease.
PP5	Not met	Not met: PP5 applies only to an exact-variant ClinVar expert-panel classification, and no expert-panel classification of this variant exists; all submissions come from clinical laboratories without expert-panel review.	clinvar
BA1	Not met	Not met: the variant's allele frequency is orders of magnitude below the >1% threshold, at 0.0016% (gnomAD v2.1) and 0.0007% (v4.1) with zero homozygotes; even the highest subpopulation frequency (0.112%) is roughly tenfold below threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the observed allele frequency (0.0016% and 0.0007%) is roughly 200-400-fold below the 0.3% threshold appropriate for this rare recessive disorder, and even the highest subpopulation frequency (0.112%) remains below it.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no healthy adult homozygous or biallelic carrier has been reported. gnomAD reports zero homozygotes, and every literature observation of the variant is in affected individuals.	gnomad_v2 gnomad_v4 PMID:18519021 PMID:16769863
BS3	Not assessed	BS3 could not be assessed: no functional study demonstrates that p.Cys253Tyr preserves parkin function, and the absence of functional characterization cannot be used as benign evidence.	PMID:25741868 PMID:18519021 PMID:16769863 oncokb
BS4	Not assessed	BS4 could not be assessed: no affected family member who lacks the variant has been reported, so there is no non-segregation evidence.	PMID:16769863
BP1	N/A	BP1 does not apply: missense variants are an established disease mechanism in PRKN, so the criterion's premise that only truncating variants cause disease does not hold for this gene.	PMID:18519021 PMID:16769863 pvs1_gene_context
BP2	Not met	Not met: PRKN disease is autosomal recessive rather than fully dominant, and the only phase-defining observation shows the variant in trans (homozygous), the opposite of the cis configuration BP2 addresses.	PMID:18519021 PMID:16769863
BP3	N/A	BP3 does not apply: the variant is a missense substitution, not an in-frame insertion/deletion in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: both calibrated missense predictors indicate a deleterious effect (REVEL 0.818, BayesDel 0.395), the opposite of the no-impact direction BP4 requires; the single no-impact signal (SpliceAI 0.00) concerns splicing only and is not sufficient.	revel bayesdel spliceai PMID:25741868 generic_acmg_combination_rules
BP5	Not assessed	BP5 could not be assessed: no proband-level data were available to determine whether an alternate molecular basis for disease exists.
BP6	Not met	Not met: BP6 applies only to an exact-variant ClinVar expert-panel Benign/Likely benign classification, and none exists; all six submissions are Pathogenic or Likely pathogenic from clinical laboratories.	clinvar
BP7	N/A	BP7 does not apply: the criterion is defined for synonymous (silent) variants, and this missense change alters the encoded protein sequence.	generic_acmg_combination_rules

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