Variant classification summary

NM_174936.4:c.137G>T

PCSK9 · NP_777596.2:p.(Arg46Leu) · NM_174936.4

GRCh37: chr1:55505647 G>T · GRCh38: chr1:55039974 G>T

Gene: PCSK9 Transcript: NM_174936.4

Final call

Benign

BS1 strong BS2 strong BP4 supporting

Variant details

Gene

PCSK9

Transcript

NM_174936.4

Protein

NP_777596.2:p.(Arg46Leu)

gnomAD AF

0.01486786579694924 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: BS1 strong is supported by a 1.65% gnomAD filtering allele frequency, above the 1% threshold.

2

Benign: BS2 strong is supported by 226 gnomAD homozygotes and adult ARIC homozygotes.

3

Benign: BP4 supporting is supported by REVEL 0.028, below the 0.29 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong benign criteria satisfy the Benign combination rule; BS1 and BS2 meet that requirement, with BP4 providing additional supporting benign evidence.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: the exact p.Arg46Leu variant is reported as a loss-of-function allele associated with lower LDL cholesterol, not as an established pathogenic variant.	PMID:16554528 clinvar
PS2	Not assessed	Not assessed: no documented de novo observation with confirmed maternity and paternity, disease phenotype, and absent family history.
PS3	Not assessed	Not assessed: exact-variant studies show lower LDL cholesterol but no validated direct functional assay demonstrating that PCSK9 p.R46L damages protein function.	PMID:16554528 PMID:26049403 PMID:33091218
PS4	Not met	Not met: exact-variant CHD data gave OR 0.503 (95% CI 0.315–0.804), whereas PS4 requires OR >5.0 with a confidence interval excluding 1.0.	PMID:16554528 PMID:33091218
PM1	Not met	Not met: no statistically significant hotspot was found at Arg46, and no supplied evidence establishes Arg46 as a critical domain without benign variation.	hotspots
PM2	Not met	Not met: gnomAD v4.1 allele frequency is 1.49%, far above the PM2 threshold of 0.01% or less.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	N/A	Not applicable: the PCSK9 disease context is autosomal dominant, whereas PM3 applies only to recessive disorders with a pathogenic variant confirmed in trans.	clinvar
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no different missense variant at residue 46 was identified as pathogenic in the supplied comparator collection.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no case-level evidence shows that the variant was assumed de novo without confirmed parental testing.
PP1	Not assessed	Not assessed: no affected relatives, matching genotypes, phenotype data, or informative meioses are documented for segregation analysis.
PP2	Not met	Not met: gnomAD v4.1 shows allele frequency 0.0148679, inconsistent with a low rate of benign missense variation in PCSK9.	gnomad_v4 PMID:29261184 PMID:21600525
PP3	Not met	Not met: REVEL 0.028 is below the supporting PP3 threshold of 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history information is available to evaluate specificity for a single-genetic-etiology disease.
PP5	Not met	Not met: ClinVar reports 0 expert-panel submissions for the exact variant, so ordinary and aggregate submissions cannot trigger PP5.	clinvar
BA1	Not met	Not met: gnomAD grpmax FAF is 1.65% in v4.1, below the 5% BA1 threshold; the higher Finnish popmax point estimate is not the required metric.	gnomad_v4 gnomad_v2 clinvar
BS1	Met	Met: gnomAD v4.1 grpmax FAF is 1.65%, above the 1% BS1 threshold, using a population with 61,024 observed alleles.	gnomad_v4 gnomad_v2 PMID:25741868 PMID:21600525
BS2	Met	Met: gnomAD v4.1 contains 226 homozygotes, and ARIC reported eight adult white homozygotes for PCSK9 R46L.	gnomad_v4 gnomad_v2 PMID:16554528
BS3	Not assessed	Not assessed: reviewed exact-variant studies provide human trait associations, not a well-established functional assay showing that PCSK9 p.R46L has no damaging effect.	PMID:16554528 PMID:26049403 PMID:33091218
BS4	Not assessed	Not assessed: no affected relatives with documented variant-negative results are available to demonstrate lack of segregation.
BP1	Not met	Not met: PCSK9 familial-hypercholesterolemia disease is associated with gain-of-function missense mutations, not primarily truncating variants.	PMID:21600525
BP2	Not assessed	Not assessed: no affected-proband observation documents a pathogenic partner variant in trans or cis with confirmed phase for this variant.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met, supporting: REVEL 0.028 is below the <=0.29 BP4 threshold for this missense variant.	revel
BP5	Not assessed	Not assessed: no case-level alternate molecular diagnosis or other molecular basis for disease is documented.
BP6	Not met	Not met: ClinVar reports 0 expert-panel submissions for the exact variant, so ordinary Benign/Likely benign submissions cannot trigger BP6.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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