PCSK9 p.Asp374Tyr

Variant names:

• chr1-55057454-G-T
• rs137852912
• NM_174936.4:c.1120G>T
• PCSK9 p.Asp374Tyr

Your query was ambiguous. Multiple possible variants found:

• chr1-55057454-G-T
• chr1-55057454-GAC-TAT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_174936.4(PCSK9):​c.1120G>T​(p.Asp374Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001422592: "In vitro functional studies demonstrating that cells transfected with the variant result in a near complete disappearance of LDLR protein provide some evidence that the p.Asp374Tyr variant may impact protein function (PMID:19081568, 15772090)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D374N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 8.03
• Publications: 261 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001422592: "In vitro functional studies demonstrating that cells transfected with the variant result in a near complete disappearance of LDLR protein provide some evidence that the p.Asp374Tyr variant may impact protein function (PMID: 19081568, 15772090)."; SCV002768238: "In vitro functional studies show that this variant results in increased binding affinity to LDLR and reduced LDLR protein levels (PMID: 17435765, 19081568)."; SCV004292328: Experimental studies have shown that this missense change affects PCSK9 function (PMID: 15358785, 16912035, 18197702, 19081568, 23283366, 27280970).; SCV004847635: "In vitro functional studies support an impact on protein function" (Benjannet 2004, Bottomley 2009, Al-Mashhadi 2013).; SCV005001970: "In multiple assays testing PCSK9 function, this variant showed functionally abnormal results (Fasano T et al. Atherosclerosis, 2009 Mar;203:166-71; Larrea-Sebal A et al. Int J Mol Sci, 2023 Feb;24:; Huijgen R et al. Arterioscler Thromb Vasc Biol, 2021 Feb;41:934-943; Sánchez-Hernández RM et al. Atherosclerosis, 2019 Oct;289:162-172)."
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-55057454-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 1-55057454-G-T is Pathogenic according to our data. Variant chr1-55057454-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.1120G>T	p.Asp374Tyr	missense	Exon 7 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.1243G>T	p.Asp415Tyr	missense	Exon 8 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.1120G>T	p.Asp374Tyr	missense	Exon 7 of 12	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1120G>T	p.Asp374Tyr	missense	Exon 7 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1477G>T	p.Asp493Tyr	missense	Exon 7 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.1243G>T	p.Asp415Tyr	missense	Exon 8 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461694 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727152

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111992

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.000332 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hypercholesterolemia, autosomal dominant, 3 (5)
3	-	-	Hypercholesterolemia, familial, 1 (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Familial hypercholesterolemia (1)
1	-	-	Homozygous familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.011	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.89
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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.

Other links and lift over

dbSNP: rs137852912;

hg19: chr1-55523127;