Genetic Variant PCSK9:p.Phe216Leu (chr1-55052400-TTC-CTT) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO5_ModerateO7_Supporting

The NM_174936.4(PCSK9):c.646_648delTTCinsCTT (p.Phe216Leu) variant causes a missense change. The gene PCSK9 is a tumor suppressor gene (CancerMine: 2 TSG, 6 oncogene, 3 driver citations). The gene PCSK9 is a known oncogene (CancerMine: 2 TSG, 6 oncogene, 3 driver citations). The gene PCSK9 is a cancer driver gene (CancerMine: 2 TSG, 6 oncogene, 3 driver citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Hypercholesterolemia, autosomal dominant, 3 (hchola3).

Frequency

Genomes: not found (cov: 32)

Consequence

PCSK9
NM_174936.4 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.27

Publications

0 publications found

Variant links:

Genes affected

PCSK9 (HGNC:20001): (proprotein convertase subtilisin/kexin type 9) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

PCSK9 Gene-Disease associations (from GenCC):

hypercholesterolemia, autosomal dominant, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PCSK9 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_174936.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Show applied only (3)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O5Same location/impact as known oncogenic		Same AA change as established oncogenic variant (or germline P/LP in TSG) — Moderate (O5); ClinVar same-AA oncogenic/T1: false \| ClinVar same-AA SCI tier: — \| CGI same-AA oncogenic: false \| TSG: true \| ClinVar same-AA germline P/LP: true \| CIViC LOF: false \| ClinVar diff-AA oncogenic: false \| ClinVar diff-AA germline P/LP: false
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 5 pathogenic, 0 benign (OR vs. background: 55.0); Variant does not impact splicing — splice-hotspot path not applicable

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_174936.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
PCSK9 NM_174936.4	MANE Select	c.646_648delTTCinsCTT p.Phe216Leu	missense	N/A	Prot: NP_777596.2
PCSK9 NM_001407240.1		c.769_771delTTCinsCTT p.Phe257Leu	missense	N/A	Prot: NP_001394169.1 UniProt: A0AAQ5BGX4
PCSK9 NM_001407241.1		c.646_648delTTCinsCTT p.Phe216Leu	missense	N/A	Prot: NP_001394170.1

PCSK9 NM_174936.4

MANE Select

HGVSc / HGVSpc.646_648delTTCinsCTTp.Phe216Leu

Exon rankN/A

missense

Prot: NP_777596.2

PCSK9 NM_001407240.1

HGVSc / HGVSpc.769_771delTTCinsCTTp.Phe257Leu

Exon rankN/A

missense

Prot: NP_001394169.1UniProt: A0AAQ5BGX4

PCSK9 NM_001407241.1

HGVSc / HGVSpc.646_648delTTCinsCTTp.Phe216Leu

Exon rankN/A

missense

Prot: NP_001394170.1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
PCSK9 ENST00000302118.5	TSL:1MANE Select	c.646_648delTTCinsCTT p.Phe216Leu	missense	N/A	Prot: ENSP00000303208.5 UniProt: Q8NBP7-1
PCSK9 ENST00000710286.1		c.1003_1005delTTCinsCTT p.Phe335Leu	missense	N/A	Prot: ENSP00000518176.1 UniProt: A0AA34QVH0
PCSK9 ENST00000713786.1		c.769_771delTTCinsCTT p.Phe257Leu	missense	N/A	Prot: ENSP00000519088.1 UniProt: A0AAQ5BGX4

PCSK9 ENST00000302118.5

TSL:1MANE Select

HGVSc / HGVSpc.646_648delTTCinsCTTp.Phe216Leu

Exon rankN/A

missense

Prot: ENSP00000303208.5UniProt: Q8NBP7-1

PCSK9 ENST00000710286.1

HGVSc / HGVSpc.1003_1005delTTCinsCTTp.Phe335Leu

Exon rankN/A

missense

Prot: ENSP00000518176.1UniProt: A0AA34QVH0

PCSK9 ENST00000713786.1

HGVSc / HGVSpc.769_771delTTCinsCTTp.Phe257Leu

Exon rankN/A

missense

Prot: ENSP00000519088.1UniProt: A0AAQ5BGX4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	5.3

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence