chr1-55052398-G-A

Variant names:

• chr1-55052398-G-A
• rs794728683
• NM_174936.4:c.644G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_174936.4(PCSK9):​c.644G>A​(p.Arg215His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,560 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: "SCV000234925: Functional studies indicate R215H is a gain-of-function mutation (Cameron et al., 2008).; SCV000766233: Experimental studies have shown that this missense change affects PCSK9 function (PMID:18266662, 18631360, 27896130).; SCV000840037: Functional studies have shown that the p.Arg215His mutant PSCK9 protein causes fewer low density lipoprotein receptors (LDLR) to be on the cell surface, thereby leading to increased levels of LDL cholesterol (PMID:18266662).; SCV004840625: An experimental study has shown no impact on catalytic peptidase function but reduced LDL uptake by ~14% (PMID:18266662, 21147780).; SCV001736420: An experimental study has shown that this variant causes no impact on catalytic peptase function, but does cause reduced LDL uptake by ~14% (PMID:18266662, 21147780).; SCV006049515: This variant was identified in one or more individuals with features consistent with familial hypercholesterolemia (FH) and segregated with disease in at least one family (Cameron, 2008). This amino acid position is well conserved in available vertebrate species. In an assay testing PCSK9 function, this variant showed a functionally abnormal result (Cameron, 2008).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1 O:1
• Conservation: PhyloP100: 2.39
• Publications: 21 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, Ambry Genetics, 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: SCV000234925: Functional studies indicate R215H is a gain-of-function mutation (Cameron et al., 2008).; SCV000766233: Experimental studies have shown that this missense change affects PCSK9 function (PMID: 18266662, 18631360, 27896130).; SCV000840037: Functional studies have shown that the p.Arg215His mutant PSCK9 protein causes fewer low density lipoprotein receptors (LDLR) to be on the cell surface, thereby leading to increased levels of LDL cholesterol (PMID: 18266662).; SCV004840625: An experimental study has shown no impact on catalytic peptidase function but reduced LDL uptake by ~14% (PMID: 18266662, 21147780).; SCV001736420: An experimental study has shown that this variant causes no impact on catalytic peptase function, but does cause reduced LDL uptake by ~14% (PMID: 18266662, 21147780).; SCV006049515: This variant was identified in one or more individuals with features consistent with familial hypercholesterolemia (FH) and segregated with disease in at least one family (Cameron, 2008). This amino acid position is well conserved in available vertebrate species. In an assay testing PCSK9 function, this variant showed a functionally abnormal result (Cameron, 2008).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_174936.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-55052397-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 633346.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 1-55052398-G-A is Pathogenic according to our data. Variant chr1-55052398-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 201127.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.644G>A	p.Arg215His	missense	Exon 4 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.767G>A	p.Arg256His	missense	Exon 5 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.644G>A	p.Arg215His	missense	Exon 4 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.644G>A	p.Arg215His	missense	Exon 4 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1001G>A	p.Arg334His	missense	Exon 4 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.767G>A	p.Arg256His	missense	Exon 5 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461560 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 727086

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

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: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000498 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.044	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.61
Sift	Benign	0.057	T
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.80		Loss of catalytic residue at R215 (P = 0.0247)
MVP		0.91
MPC		0.55
ClinPred		0.89	D
GERP RS		0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.16
gMVP		0.54
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs794728683; hg19: chr1-55518071;