rs794728683

Positions:

• chr1-55052398-G-A
• chr1-55052398-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215S) 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1 O:1
• Conservation: PhyloP100: 2.39

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-55052397-C-A is described in Lovd as [Likely_pathogenic].
• 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 [Likely_pathogenic]. Clinvar id is 201127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55052398-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.644G>A	p.Arg215His	missense_variant	4/12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.644G>A	p.Arg215His	missense_variant	4/12	1	NM_174936.4	ENSP00000303208	P2

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Pathogenic:3 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces arginine with histidine at codon 215 in the catalytic peptidase domain of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental study has shown no impact on catalytic peptidase function but reduced LDL uptake by ~14% (PMID: 18266662, 21147780). A different study has shown no significant impact on the LDL uptake by the mutant protein (PMID: 27896130). The clinical relevance of this observation is not known. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 18266662, 18266662, 26633542, 28008010, 34037665, 36980993). It has been shown that this variant segregates with disease in more than 20 individuals affected with hypercholesterolemia from two Norwegian families (PMID: 18266662, 26374825). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 05, 2017	This variant has been reported to segregate with hypercholesterolemia in a single family (PMID: 18266662). ClinVar contains an entry for this variant (Variation ID: 201127). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change does not get cleaved by furin and therefore prevents regular PCSK9 inactivation leading to a PCSK9 protein more active than wild-type (PMID: 18266662, 18631360, 27896130). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 215 of the PCSK9 protein (p.Arg215His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 21, 2017	This c.644G>A (p.Arg215His) variant in the PCSK9 gene has been reported in 3 unrelated patients with hypercholesterolemia (PMID: 18266662, 28008010). In the family of one of these patients, this variant segregated with hypercholesterolemia in eight relatives (PMID: 18266662). A different amino acid substitution, arginine to lysine at residue 215 of the PCSK9 protein, has also been reported as disease-causing in 1 patient with familial hypercholesterolemia (PMID: 25962062). 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). This variant is classified as likely pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -

Homozygous familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 08, 2018

The p.Arg215His variant in PCSK9 has been reported in at least 5 individuals with hypercholesterolemia, segregated with disease in at least 20 affected relatives from 2 families (Cameron 2008, Hopkins 2015, Retterer 2015, Abul-Husn 2016), and was absent from large population studies. In vitro functional studies provide conflicting evidence as to whether the p.Arg215His variant may impact protein function (Cameron 2008, Wierod 2016). However, these types of assays may not accurately represent biological function. This variant is reported in ClinVar (Variation ID: 201127). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg215His variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Supporting. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2016

The R215H mutation in the PCSK9 gene has been reported previously in two unrelated probands (Cameron et al., 2008). R215H co-segregated with hypercholesterolemia in eight relatives from one family and functional studies indicate R215H is a gain-of-function mutation (Cameron et al., 2008). Mutations in nearby residues (F216L, R218S) have been reported in association with hypercholesterolemia, further supporting the functional importance of this region of the protein. The R215H mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R215H as a disease-causing mutation. The variant is found in the PCSK9 panel(s). -

Familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 03, 2023

This missense variant replaces arginine with histidine at codon 215 in the catalytic peptidase domain of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental study has shown no impact on catalytic peptidase function but reduced LDL uptake by ~14% (PMID: 18266662, 21147780). A different study has shown no significant impact on the LDL uptake by the mutant protein (PMID: 27896130). The clinical relevance of this observation is not known. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 18266662, 18266662, 26633542, 28008010, 34037665, 36980993). It has been shown that this variant segregates with disease in more than 20 individuals affected with hypercholesterolemia from two Norwegian families (PMID: 18266662, 26374825). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.79	D;D;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728683; hg19: chr1-55518071;