VCV000265933.46 - ClinVar

NM_174936.4(PCSK9):c.709C>T (p.Arg237Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(18)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(9); Likely benign(6)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_174936.4(PCSK9):c.709C>T (p.Arg237Trp)

Variation ID: 265933 Accession: VCV000265933.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p32.3 1: 55052701 (GRCh38) [ NCBI UCSC ] 1: 55518374 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 15, 2016	Oct 20, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_174936.4:c.709C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_777596.2:p.Arg237Trp	missense
NM_001407240.1:c.832C>T	NP_001394169.1:p.Arg278Trp	missense
NM_001407241.1:c.709C>T	NP_001394170.1:p.Arg237Trp	missense
NM_001407242.1:c.712C>T	NP_001394171.1:p.Arg238Trp	missense
NM_001407243.1:c.652C>T	NP_001394172.1:p.Arg218Trp	missense
NM_001407244.1:c.709C>T	NP_001394173.1:p.Arg237Trp	missense
NM_001407245.1:c.517C>T	NP_001394174.1:p.Arg173Trp	missense
NM_001407246.1:c.334C>T	NP_001394175.1:p.Arg112Trp	missense
NM_001407247.1:c.709C>T	NP_001394176.1:p.Arg237Trp	missense
NR_110451.3:n.1042C>T
NR_176318.1:n.683C>T
NR_176319.1:n.999C>T
NR_176320.1:n.1122C>T
NR_176321.1:n.999C>T
NR_176322.1:n.999C>T
NR_176323.1:n.999C>T
NR_176324.1:n.1261C>T
NC_000001.11:g.55052701C>T
NC_000001.10:g.55518374C>T
NG_009061.1:g.18155C>T
LRG_275:g.18155C>T
LRG_275t1:c.709C>T	LRG_275p1:p.Arg237Trp
	Q8NBP7:p.Arg237Trp

... more HGVS ... less HGVS

Protein change

R237W, R238W, R112W, R173W, R278W, R218W

Other names

Canonical SPDI

NC_000001.11:55052700:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00020

Exome Aggregation Consortium (ExAC) 0.00060

The Genome Aggregation Database (gnomAD) 0.00066

The Genome Aggregation Database (gnomAD), exomes 0.00072

Trans-Omics for Precision Medicine (TOPMed) 0.00088

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00108

Links

ClinGen: CA044076 UniProtKB: Q8NBP7#VAR_025452 dbSNP: rs148195424 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PCSK9		Dosage sensitivity unlikely	No evidence available	GRCh38 GRCh37	1275	1289

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hypercholesterolemia, familial, 1	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Aug 22, 2019	RCV000256274.14
Hypercholesterolemia, autosomal dominant, 3	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Feb 1, 2024	RCV000417261.24
Familial hypercholesterolemia	Likely benign (1)	criteria provided, single submitter	Aug 23, 2019	RCV000771113.12
Hypobetalipoproteinemia	Uncertain significance (1)	criteria provided, single submitter	Apr 28, 2017	RCV001099242.12
not specified	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 4, 2022	RCV001194053.12
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Sep 1, 2023	RCV001284675.29
Short fetal femur length	Uncertain significance (1)	no assertion criteria provided	-	RCV002463441.8
PCSK9-related disorder	Likely benign (1)	no assertion criteria provided	Feb 2, 2024	RCV004535242.2
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Jun 30, 2021	RCV002365275.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000323052.1 First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016	Publications: PubMed (1) PubMed: 16571601 Comment: 0/190 non-FH alleles (portuguese normolipidemic individuals); 0/100 normolipidemic individuals Observation 1: Comment on evidence: %MAF (ExAC):0.05973 Observation 2: Comment on evidence: Heterologous cells (HepG2), FACS and WB assays / (HEK), pulse-chase [35S]Met/Cys assays Result: Increase 16-35% LDLR activity (+ 15-20% LDLR at cell surface, +25-30% LDL internalization); normal PCSK9 autocatalytic activity / normal (80-100%) PCSK9 processing
Uncertain significance (Dec 16, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, autosomal dominant, 3 Affected status: yes Allele origin: germline	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix Accession: SCV000503510.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: subjects mutated among 2600 FH index cases screened = 2, family member = 1 / Software predictions: Damaging
Uncertain significance (Aug 22, 2019)	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016)) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Robarts Research Institute, Western University Accession: SCV000484816.2 First in ClinVar: Oct 15, 2016 Last updated: Sep 11, 2019	Publications: PubMed (1) PubMed: 27765764 Number of individuals with the variant: 1
Uncertain significance (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypobetalipoproteinemia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001255678.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 16912035‚ 16424354‚ 16571601 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypercholesterolemia, autosomal dominant, 3 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001255679.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (4) PubMed: 16912035‚ 16571601‚ 17765244‚ 16465619 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (May 16, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001363300.2 First in ClinVar: Jun 22, 2020 Last updated: May 21, 2021	Publications: PubMed (28) PubMed: 18710658‚ 15358785‚ 16465619‚ 16424354‚ 16571601‚ 17971861‚ 22923420‚ 26636822‚ 19001363‚ 24507775‚ 25412415‚ 26020417‚ 17804797‚ 18197702‚ 23386946‚ 29459468‚ 29593013‚ 16912035‚ 28438747‚ 18266662‚ 18300938‚ 17765244‚ 25046268‚ 17502126‚ 20959675‚ 17140581‚ 18262190‚ 26546829 Comment: Variant summary: PCSK9 c.709C>T (p.Arg237Trp) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five … (more) Variant summary: PCSK9 c.709C>T (p.Arg237Trp) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 249096 control chromosomes. The observed variant frequency is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05), strongly suggesting that the variant is benign. c.709C>T has been reported in the literature in sequencing studies of individuals affected with hypercholesterolemia (e.g. Kotowski_2006, Homer_2008, Madeiros_2016, Berge_2006, Cameron_2008, Leren_2008, Lange_2014, Benn_2017, Balder_2018) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At-least one co-occurrence with another pathogenic variant causative of Familial Hypercholesterolemia has been observed at our laboratory (LDLR c.2043C>A, p.Cys681*), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. One group reports little to no damaging effects for the variant in the processing and secretion of PCSK9 protein (Benjannet_2004, Benjannet_2006). Another study reports a very mild increase in the expression of LDL receptor on the cell surface and slightly higher levels of LDL internalization in cells with the variant (Cameron_2006). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=6). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Likely benign (Aug 23, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000902818.3 First in ClinVar: May 20, 2019 Last updated: Jan 12, 2022	Comment: This variant has been identified in 0.2200% (62/28178) of Color clients and in 0.1327% (47/35392) of Latino population in the Genome Aggregation Database (gnomAD). This … (more) This variant has been identified in 0.2200% (62/28178) of Color clients and in 0.1327% (47/35392) of Latino population in the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for PCSK9-related disorders based on prevalence, penetrance, and genetic heterogeneity. Therefore, this variant is classified as Likely Benign. (less)
Likely benign (Dec 28, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001470596.2 First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024	Publications: PubMed (12) PubMed: 27765764‚ 16465619‚ 16571601‚ 24507775‚ 16424354‚ 29259136‚ 18262190‚ 17765244‚ 20623344‚ 33303402‚ 33231818‚ 15358785
Likely benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypercholesterolemia, autosomal dominant, 3 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001002323.5 First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024
Uncertain significance (Jun 09, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715291.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Number of individuals with the variant: 1
Uncertain significance (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002518457.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Uncertain significance (Oct 26, 2021)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Hypercholesterolemia, autosomal dominant, 3 Affected status: unknown Allele origin: germline	New York Genome Center Accession: SCV002764436.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Comment: The c.709C>T (p.Arg237Trp) variant identified in the PCSK9 gene substitutes a conserved Arginine for Tryptophan at amino acid 237/693 (exon5/12). This variant is found in … (more) The c.709C>T (p.Arg237Trp) variant identified in the PCSK9 gene substitutes a conserved Arginine for Tryptophan at amino acid 237/693 (exon5/12). This variant is found in 99 heterozygotes in gnomAD(v3.1.1) (0 homozygotes; allele frequency:6.5e-4), which is slightly higher than expected for a pathogenic Familial Hypercholesterolemia associated variant (ClinGen Familial Hypercholesterolemia Expert Panel Specifications, Version 1.1). In silico algorithms predict this variant to be Pathogenic (REVEL; score:0.615) and Damaging (SIFT; score:0.001) to the function of the canonical transcript. This variant is reported in ClinVar as both a Variant of Uncertain Significance and Likely Benign (VarID:265933). The p.Arg237Trp variant has been reported in individuals in the literature with hypercholesterolemia [PMID:26020417, 18262190, 16465619, 33418990], but has also been identified in many individuals with hypocholesterolemia [PMID:29459468,24507775, 20623344, 16424354, others]. Functional studies on the role of this variant to PCSK9 function are conflicting, with some studies suggesting no damaging effect on PCSK9 [PMID:15358785, 29259136], and another suggesting mild increase in LDL receptor and higher LDL internalization possibly due to failure to undergo autocatalytic cleavage [PMID:16571601]. The p.Arg237 residue is within the Peptidase S8 domain of PCSK9 (UniProtKB:Q8NBP7). Given the conflicting informationregarding the c.709C>T (p.Arg237Trp) variant identified in the PCSK9 gene, it is reported as a Variant of Uncertain Significance. (less) Clinical Features: Hyperlipidemia (present) Secondary finding: no
Uncertain significance (May 26, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001874182.3 First in ClinVar: Sep 19, 2021 Last updated: Mar 04, 2023	Comment: Also identified in patients with hypercholesterolemia in published literature (de Paiva Silvino et al., 2020; Gill et al., 2021; Meshkov et al., 2021); at least … (more) Also identified in patients with hypercholesterolemia in published literature (de Paiva Silvino et al., 2020; Gill et al., 2021; Meshkov et al., 2021); at least one patient also harbored a pathogenic variant in the LDLR gene (Wang et al., 2016); Published functional studies demonstrate loss-of-function with a modest effect, resulting in a 16% increased level of cell surface LDL-receptors and a 35% increase in the internalization of LDL when compared to wild-type PCSK9 (Cameron et al., 2006); This variant is associated with the following publications: (PMID: 18300938, 25046268, 16424354, 16465619, 17765244, 21943799, 28157721, 17435765, 16912035, 15358785, 24507775, 27535533, 16571601, 26582918, 27765764, 33418990, 33231818, 33303402) (less)
Likely benign (Jun 30, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002663096.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Sep 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004042432.11 First in ClinVar: Oct 14, 2023 Last updated: Oct 20, 2024	Comment: PCSK9: BS1 Number of individuals with the variant: 1
Uncertain significance (Aug 01, 2016)	no assertion criteria provided Method: research	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: CSER - NEXT Medicine variant annotation Accession: SCV000503554.1 First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016	Comment: Found in patient having exome sequencing for an unrelated indication. No known history of hyperlipidemia.
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	Short fetal femur length Affected status: yes Allele origin: unknown	Phenosystems SA Accession: SCV002757888.1 First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022	Number of individuals with the variant: 1
Likely benign (Feb 02, 2024)	no assertion criteria provided Method: clinical testing	PCSK9-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004743984.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Variant summary: PCSK9 c.709C>T (p.Arg237Trp) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 249096 control chromosomes. The observed variant frequency is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05), strongly suggesting that the variant is benign. c.709C>T has been reported in the literature in sequencing studies of individuals affected with hypercholesterolemia (e.g. Kotowski_2006, Homer_2008, Madeiros_2016, Berge_2006, Cameron_2008, Leren_2008, Lange_2014, Benn_2017, Balder_2018) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At-least one co-occurrence with another pathogenic variant causative of Familial Hypercholesterolemia has been observed at our laboratory (LDLR c.2043C>A, p.Cys681*), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. One group reports little to no damaging effects for the variant in the processing and secretion of PCSK9 protein (Benjannet_2004, Benjannet_2006). Another study reports a very mild increase in the expression of LDL receptor on the cell surface and slightly higher levels of LDL internalization in cells with the variant (Cameron_2006). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=6). Based on the evidence outlined above, the variant was classified as likely benign.

Comment:

This variant has been identified in 0.2200% (62/28178) of Color clients and in 0.1327% (47/35392) of Latino population in the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for PCSK9-related disorders based on prevalence, penetrance, and genetic heterogeneity. Therefore, this variant is classified as Likely Benign.

Comment:

The c.709C>T (p.Arg237Trp) variant identified in the PCSK9 gene substitutes a conserved Arginine for Tryptophan at amino acid 237/693 (exon5/12). This variant is found in 99 heterozygotes in gnomAD(v3.1.1) (0 homozygotes; allele frequency:6.5e-4), which is slightly higher than expected for a pathogenic Familial Hypercholesterolemia associated variant (ClinGen Familial Hypercholesterolemia Expert Panel Specifications, Version 1.1). In silico algorithms predict this variant to be Pathogenic (REVEL; score:0.615) and Damaging (SIFT; score:0.001) to the function of the canonical transcript. This variant is reported in ClinVar as both a Variant of Uncertain Significance and Likely Benign (VarID:265933). The p.Arg237Trp variant has been reported in individuals in the literature with hypercholesterolemia [PMID:26020417, 18262190, 16465619, 33418990], but has also been identified in many individuals with hypocholesterolemia [PMID:29459468,24507775, 20623344, 16424354, others]. Functional studies on the role of this variant to PCSK9 function are conflicting, with some studies suggesting no damaging effect on PCSK9 [PMID:15358785, 29259136], and another suggesting mild increase in LDL receptor and higher LDL internalization possibly due to failure to undergo autocatalytic cleavage [PMID:16571601]. The p.Arg237 residue is within the Peptidase S8 domain of PCSK9 (UniProtKB:Q8NBP7). Given the conflicting informationregarding the c.709C>T (p.Arg237Trp) variant identified in the PCSK9 gene, it is reported as a Variant of Uncertain Significance.

Comment:

Also identified in patients with hypercholesterolemia in published literature (de Paiva Silvino et al., 2020; Gill et al., 2021; Meshkov et al., 2021); at least one patient also harbored a pathogenic variant in the LDLR gene (Wang et al., 2016); Published functional studies demonstrate loss-of-function with a modest effect, resulting in a 16% increased level of cell surface LDL-receptors and a 35% increase in the internalization of LDL when compared to wild-type PCSK9 (Cameron et al., 2006); This variant is associated with the following publications: (PMID: 18300938, 25046268, 16424354, 16465619, 17765244, 21943799, 28157721, 17435765, 16912035, 15358785, 24507775, 27535533, 16571601, 26582918, 27765764, 33418990, 33231818, 33303402)

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia.	Gill PK	Journal of clinical lipidology	2021	PMID: 33303402
Cascade screening and genetic diagnosis of familial hypercholesterolemia in clusters of the Southeastern region from Brazil.	de Paiva Silvino JP	Molecular biology reports	2020	PMID: 33231818
Relationship of Familial Hypercholesterolemia and High Low-Density Lipoprotein Cholesterol to Ischemic Stroke: Copenhagen General Population Study.	Beheshti S	Circulation	2018	PMID: 29593013
Genetics, Lifestyle, and Low-Density Lipoprotein Cholesterol in Young and Apparently Healthy Women.	Balder JW	Circulation	2018	PMID: 29459468
Stepwise processing analyses of the single-turnover PCSK9 protease reveal its substrate sequence specificity and link clinical genotype to lipid phenotype.	Chorba JS	The Journal of biological chemistry	2018	PMID: 29259136
Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer's disease and Parkinson's disease: Mendelian randomisation study.	Benn M	BMJ (Clinical research ed.)	2017	PMID: 28438747
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.	Wang J	Arteriosclerosis, thrombosis, and vascular biology	2016	PMID: 27765764
Update on the molecular biology of dyslipidemias.	Ramasamy I	Clinica chimica acta; international journal of clinical chemistry	2016	PMID: 26546829
Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement.	Medeiros AM	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26020417
Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel.	Celestino-Soper PB	PloS one	2015	PMID: 26636822
Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians.	Tsai CW	The Journal of clinical endocrinology and metabolism	2015	PMID: 25412415
PCSK9 inhibition in LDL cholesterol reduction: genetics and therapeutic implications of very low plasma lipoprotein levels.	Marais AD	Pharmacology & therapeutics	2015	PMID: 25046268
Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.	Lange LA	American journal of human genetics	2014	PMID: 24507775
Mutation in the PCSK9 Gene in Omani Arab Subjects with Autosomal Dominant Hypercholesterolemia and its Effect on PCSK9 Protein Structure.	Al-Waili K	Oman medical journal	2013	PMID: 23386946
Pooled DNA resequencing of 68 myocardial infarction candidate genes in French canadians.	Beaudoin M	Circulation. Cardiovascular genetics	2012	PMID: 22923420
A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo.	Ni YG	Journal of lipid research	2011	PMID: 20959675
The influence of PCSK9 polymorphisms on serum low-density lipoprotein cholesterol and risk of atherosclerosis.	Davignon J	Current atherosclerosis reports	2010	PMID: 20623344
Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants.	Bottomley MJ	The Journal of biological chemistry	2009	PMID: 19001363
Identification of mutations in the apolipoprotein B-100 gene and in the PCSK9 gene as the cause of hypocholesterolemia.	Leren TP	Clinica chimica acta; international journal of clinical chemistry	2008	PMID: 18710658
Molecular population genetics of PCSK9: a signature of recent positive selection.	Ding K	Pharmacogenetics and genomics	2008	PMID: 18300938
Characterization of novel mutations in the catalytic domain of the PCSK9 gene.	Cameron J	Journal of internal medicine	2008	PMID: 18266662
Genetic variation at the PCSK9 locus moderately lowers low-density lipoprotein cholesterol levels, but does not significantly lower vascular disease risk in an elderly population.	Polisecki E	Atherosclerosis	2008	PMID: 18262190
Self-association of human PCSK9 correlates with its LDLR-degrading activity.	Fan D	Biochemistry	2008	PMID: 18197702
Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa.	Homer VM	Atherosclerosis	2008	PMID: 17765244
Evidence for positive selection in the C-terminal domain of the cholesterol metabolism gene PCSK9 based on phylogenetic analysis in 14 primate species.	Ding K	PloS one	2007	PMID: 17971861
The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain.	Hampton EN	Proceedings of the National Academy of Sciences of the United States of America	2007	PMID: 17804797
Of PCSK9, cholesterol homeostasis and parasitic infections: possible survival benefits of loss-of-function PCSK9 genetic polymorphisms.	Mbikay M	Medical hypotheses	2007	PMID: 17502126
Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.	Pisciotta L	Atherosclerosis	2007	PMID: 17140581
The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.	Benjannet S	The Journal of biological chemistry	2006	PMID: 16912035
Effect of mutations in the PCSK9 gene on the cell surface LDL receptors.	Cameron J	Human molecular genetics	2006	PMID: 16571601
A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.	Kotowski IK	American journal of human genetics	2006	PMID: 16465619
Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy.	Berge KE	Arteriosclerosis, thrombosis, and vascular biology	2006	PMID: 16424354
NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.	Benjannet S	The Journal of biological chemistry	2004	PMID: 15358785
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Text-mined citations for rs148195424 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_174936.4(PCSK9):c.709C>T (p.Arg237Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs148195424 ...