NM_001009944.3:c.9850T>C

PKD1 · NP_001009944.3:p.(Cys3284Arg) · NM_001009944.3

GRCh37: chr16:2149935 A>G · GRCh38: chr16:2099934 A>G

Gene: PKD1 Transcript: NM_001009944.3

Final call

VUS

PM2 moderate PP3 supporting

Variant details

Gene

PKD1

Transcript

NM_001009944.3

Protein

NP_001009944.3:p.(Cys3284Arg)

gnomAD AF

0.0 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001009944.3:c.9850T>C (p.Cys3284Arg) is a missense variant in PKD1, associated with autosomal dominant polycystic kidney disease (ADPKD).

This variant is absent from gnomAD v4.1 (0/1,562,318 alleles), gnomAD v2.1, and gnomAD-Canada v1.0, meeting PM2 at moderate strength.

REVEL meta-predictor score of 0.754 supports a deleterious effect, meeting PP3 at supporting strength.

ClinVar contains a single submission (SCV004239210, Labor Dr. Heidrich & Kollegen MVZ GmbH) classifying this variant as Likely pathogenic, but with no assertion criteria provided; this is insufficient to meet PS5 or PP5.

With only PM2 (moderate) and PP3 (supporting) met, the variant does not reach the threshold for Likely Pathogenic under generic ACMG/AMP 2015 combination rules (PMID:25741868). PM2 + PP3 alone constitutes a Variant of Uncertain Significance. No benign criteria are met.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_001009944.3:c.9850T>C is a missense variant (p.Cys3284Arg). It does not fall into the null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus) required for PVS1 application under the generic ClinGen SVI PVS1 framework (PMC6185798). The PKD1 CSPEC VCEP framework (v1.0.0) is in preparation and contains no PVS1 override rules.	pvs1_generic_framework
PS1	Not assessed	No evidence of a different nucleotide change at codon 3284 with an established pathogenic classification was identified. PS1 requires a previously classified pathogenic variant causing the same amino acid change.
PS2	Not assessed	No de novo occurrence data with confirmed maternity and paternity were identified for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies were identified for NM_001009944.3:c.9850T>C (p.Cys3284Arg).
PS4	Not assessed	Insufficient data to assess variant prevalence in affected individuals vs controls. A single ClinVar submission classifies this variant as Likely pathogenic (SCV004239210, Molecular Genetics, Labor Dr. Heidrich & Kollegen MVZ GmbH) but provides no assertion criteria and no case-level detail.	clinvar
PS5	Not met	ClinVar lists one clinical laboratory submission classifying this variant as Likely pathogenic (SCV004239210), but the submission provides no assertion criteria and has a trust tier of 'weak.' A single submission without documented evidence does not meet the PS5 threshold for a reputable source reporting the variant as pathogenic with unavailable primary evidence.	clinvar
PM1	Not assessed	The variant does not lie in a statistically significant mutational hotspot per the Cancer Hotspots database. No domain-level functional data are available to assess whether codon 3284 resides in a critical, well-established functional domain of polycystin-1.
PM2	Met	This variant is absent from large population databases. In gnomAD v4.1, it is absent in 1,562,318 alleles (0 homozygotes, AF = 0%), absent in gnomAD v2.1, and absent in gnomAD-Canada v1.0. Using generic ACMG/AMP thresholds (PM2: AF < 0.1% with confirmed absence), this meets moderate evidence for pathogenicity.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not assessed	No pathogenic missense comparators at codon 3284 were identified through automated ClinVar harvesting. PM5 requires a different pathogenic missense variant at the same amino acid residue.
PM6	Not assessed	No de novo occurrence data (without confirmation of paternity and maternity) were identified for this variant. PM6 requires at least an assumed de novo observation.
PP1	Not assessed	No co-segregation data with disease in multiple affected family members were identified.
PP2	Not assessed	PKD1 is known to harbor pathogenic missense variants in ADPKD, but gene-level missense constraint data (e.g., missense Z-score, HCI prior) were not available to formally assess a low rate of benign missense variation. HCI prior lookup returned no result.
PP3	Met	REVEL, a meta-predictor integrating multiple computational methods, scores this variant at 0.754, which exceeds the commonly used pathogenic threshold of 0.5 and supports a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel score (0.242) falls in the uncertain range and does not independently support pathogenicity. REVEL alone provides sufficient computational support for PP3 at the supporting level.	revel bayesdel spliceai
PP4	Not assessed	No patient-specific phenotypic data or family history information were available to assess whether the phenotype is highly specific for ADPKD with a single genetic etiology.
PP5	Not met	Same as PS5: a single ClinVar submission classifies this variant as Likely pathogenic without assertion criteria, which does not meet the PP5 threshold for a reputable source report.	clinvar
BA1	Not met	Global minor allele frequency is 0.0% in gnomAD v4.1, far below the 1% threshold for BA1. The variant is absent from all population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Global minor allele frequency is 0.0%, far below the 0.3% threshold for BS1 in a dominant disorder. The variant is absent from all population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on observation of this variant in healthy adult individuals in the absence of ADPKD. While gnomAD absence is consistent with rarity, it does not directly provide the healthy adult observation required for BS2.
BS3	Not assessed	No well-established in vitro or in vivo functional studies showing no deleterious effect were identified for this variant.
BS4	Not assessed	No segregation data demonstrating lack of co-segregation with disease were available.
BP1	N/A	PKD1-associated ADPKD is caused by both missense and truncating variants; the gene is not limited to a primarily truncating disease mechanism. BP1 is not applicable.
BP2	Not assessed	No observation of this variant in trans with a known pathogenic dominant PKD1 variant was identified.
BP4	Not met	REVEL score of 0.754 predicts a deleterious effect, contradicting the requirement for multiple lines of computational evidence suggesting no impact on gene product. SpliceAI (max delta 0.0) shows no splicing effect, but REVEL alone precludes BP4 application.	revel bayesdel spliceai
BP5	Not assessed	No case was identified where this variant was found in an individual with an alternate molecular basis for disease.
BP6	Not met	ClinVar classifies this variant as Likely pathogenic (1 submitter), not benign. BP6 requires a reputable source to report the variant as benign.	clinvar
BP7	N/A	This is a missense variant (c.9850T>C, p.Cys3284Arg), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact.
BP3	N/A	Skipped: BP3 applies to in-frame indels in repetitive regions; this is a substitution variant.
PM3	N/A	Skipped: PM3 applies to recessive disorders (variants in trans); PKD1-associated ADPKD is autosomal dominant.
PM4	N/A	Skipped: PM4 applies to protein length-altering variants (indels, stop-loss); this is a substitution variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.