rs778738291

Variant names:

• chr1-55044020-G-A
• rs778738291
• NM_174936.4:c.385G>A
• PCSK9 p.Asp129Asn

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPM5PP5BP4

The NM_174936.4(PCSK9):c.385G>A (p.Asp129Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000805 (AC=13) in the gnomAD database across 1,614,046 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). ClinVar reports functional evidence for this variant: "SCV000965292: Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PCSK9 function (PMID:19081568, 23064986, 26195630, 34948399)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.D129G: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 438332) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D129= (synonymous): Likely_benign (ClinVar VariationId 1670793, 2 stars)

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:6 B:1
• Conservation: PhyloP100: 4.79
• Publications: 13 publications found

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000965292: Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PCSK9 function (PMID: 19081568, 23064986, 26195630, 34948399).; SCV005202937: "In vitro experiments carried out in HEK293 and HepG2 cell lines found this variant to have a relatively mild gain-of-function impact on the activity of PCSK9 (example, Ahmad_2012, Chorba_2018, Fasano_2009, Uribe_2021)." PMID: 23064986, 34407635, 36338372, 29259136, 19081568, 34948399
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 1 benign (OR vs. background: 8.3).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000137 by highest known P/LP ClinVar AF 0.000137) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.D129G: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 438332); Other variants at the same amino acid residue (not pathogenic): p.D129= (synonymous): Likely_benign (ClinVar VariationId 1670793, 2 stars)
	PP5Reputable source reports pathogenic		ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PCSK9 NM_174936.4	MANE Select	c.385G>A p.Asp129Asn	missense	Exon 2 of 12	Prot: NP_777596.2
	PCSK9 NM_001407240.1		c.508G>A p.Asp170Asn	missense	Exon 3 of 13	Prot: NP_001394169.1 UniProt:
	PCSK9 NM_001407241.1		c.385G>A p.Asp129Asn	missense	Exon 2 of 12	Prot: NP_001394170.1

PCSK9 NM_174936.4

MANE Select

HGVSc / HGVSpc.385G>Ap.Asp129Asn

Exon rankExon 2 of 12

missense

Prot: NP_777596.2

PCSK9 NM_001407240.1

HGVSc / HGVSpc.508G>Ap.Asp170Asn

Exon rankExon 3 of 13

missense

Prot: NP_001394169.1UniProt: A0AAQ5BGX4

PCSK9 NM_001407241.1

HGVSc / HGVSpc.385G>Ap.Asp129Asn

Exon rankExon 2 of 12

missense

Prot: NP_001394170.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PCSK9 ENST00000302118.5	TSL:1MANE Select	c.385G>A p.Asp129Asn	missense	Exon 2 of 12	Prot: ENSP00000303208.5 UniProt:
	PCSK9 ENST00000710286.1		c.742G>A p.Asp248Asn	missense	Exon 2 of 12	Prot: ENSP00000518176.1 UniProt:
	PCSK9 ENST00000713786.1		c.508G>A p.Asp170Asn	missense	Exon 3 of 13	Prot: ENSP00000519088.1 UniProt:

PCSK9 ENST00000302118.5

TSL:1MANE Select

HGVSc / HGVSpc.385G>Ap.Asp129Asn

Exon rankExon 2 of 12

missense

Prot: ENSP00000303208.5UniProt: Q8NBP7-1

PCSK9 ENST00000710286.1

HGVSc / HGVSpc.742G>Ap.Asp248Asn

Exon rankExon 2 of 12

missense

Prot: ENSP00000518176.1UniProt: A0AA34QVH0

PCSK9 ENST00000713786.1

HGVSc / HGVSpc.508G>Ap.Asp170Asn

Exon rankExon 3 of 13

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152186	Cov:33
GnomAD2 exomes	AF: 0.0000159	AC:4	Hom:	AN:251360	Cov:
GnomAD4 exome	AF: 0.00000821	AC:12	Hom:0	AN:1461860	Cov:32
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152186	Cov:33
TOPMed (Bravo)	AF: 0.0000189	AC:5	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000616	AC:4	Hom:0	AN:64926	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122724	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.0000148	1	67400	0.00	0	132416

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	Hypercholesterolemia, autosomal dominant, 3 (5)
2	1	-	Familial hypercholesterolemia (3)
-	3	-	not provided (3)
1	-	1	Hypercholesterolemia, familial, 1 (2)
-	1	-	Cardiovascular phenotype (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	18
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.045
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.90	D
FuncVEP CTI	Benign	0.16
GPN-Star LLR	N/A	-4.1
GPN-Star score	N/A	4.1
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.77	T
Mutation Taster	N/A	53/47	disease causing (ClinVar)
MutationAssessor	Uncertain	2.2	M
PhyloP100	Uncertain	4.8
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.22
Sift	Benign	0.25	T
Sift4G	Benign	0.097	T
Varity_R	N/A	0.34
VESM-3B	Benign	-7.6

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs778738291;

hg19: chr1-55509693;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar