1-55039879-ACTGCTGCTG-ACTGCTGCTGCTG

Variant names:

• chr1-55039879-A-ACTG
• rs35574083
• NM_174936.4:c.63_65dupGCT

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.63_65dupGCT​(p.Leu22dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,557,874 control chromosomes in the GnomAD database, including 14,501 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L22L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (1818 hom., cov: 31)
  • Exomes 𝑓: 0.14 (12683 hom.)
• Consequence: PCSK9 NM_174936.4 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.246
• Publications: 14 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_174936.4
• BP6: Variant 1-55039879-A-ACTG is Benign according to our data. Variant chr1-55039879-A-ACTG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.63_65dupGCT	p.Leu22dup	disruptive_inframe_insertion	Exon 1 of 12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.63_65dupGCT	p.Leu22dup	disruptive_inframe_insertion	Exon 1 of 12	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23110 AN: 152038 Hom.: 1811 Cov.: 31

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0863

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.122 AC: 19607 AN: 161082 AF XY: 0.123

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.0770

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.0898

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.140 AC: 197297 AN: 1405720 Hom.: 12683 Cov.: 30 AF XY: 0.140 AC XY: 97431 AN XY: 694280

African (AFR) AF: 0.201 AC: 6452 AN: 32166

American (AMR) AF: 0.0817 AC: 2993 AN: 36632

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4189 AN: 25156

East Asian (EAS) AF: 0.122 AC: 4506 AN: 36930

South Asian (SAS) AF: 0.146 AC: 11644 AN: 79788

European-Finnish (FIN) AF: 0.0938 AC: 4583 AN: 48876

Middle Eastern (MID) AF: 0.125 AC: 595 AN: 4746

European-Non Finnish (NFE) AF: 0.142 AC: 154204 AN: 1083118

Other (OTH) AF: 0.139 AC: 8131 AN: 58308

GnomAD4 genome AF: 0.152 AC: 23137 AN: 152154 Hom.: 1818 Cov.: 31 AF XY: 0.148 AC XY: 11020 AN XY: 74402

African (AFR) AF: 0.208 AC: 8628 AN: 41518

American (AMR) AF: 0.108 AC: 1650 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 593 AN: 3466

East Asian (EAS) AF: 0.114 AC: 591 AN: 5162

South Asian (SAS) AF: 0.150 AC: 726 AN: 4824

European-Finnish (FIN) AF: 0.0863 AC: 914 AN: 10596

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9434 AN: 67976

Other (OTH) AF: 0.144 AC: 303 AN: 2110

Alfa AF: 0.0742 Hom.: 92

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 30, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. c.63_65dupGCT in PCKS9 (aka c.61_63dupCTG, c.43_44insCTG, L21dup, L10, p.L15_16insL). This is an in-frame duplication of three nucleotides which results in insertion of a leucine in a 9-leucine track. The variant has been seen in at least 8 unrelated cases of familial hypercholesterolemia however it has also been observed at appreciable frequencies in individuals from the general population with normal cholesterol. Noguchi et al (2010) reported that 8 of 55 familial hypercholesterolemia patients without LDLR variants were heterozygous for this variant. No segregation or control data was provided. In total the variant has been seen in the homozygous state in 11 of 822 individuals and in the heterozygous state in 204 of 822 individuals from published reports and publicly available population datasets. The variant is listed in dbSNP as rs35574083 without minor allele frequency data. Another dbSNP entry, rs45454392, also represents a leucine insertion in the same track of leucine repeats, denoted c.44_45insGCT (p.Leu15delinsLeuLeu). These variants are likely synonymous as it would be impossible to know exactly where the insertion occurred in the repeat track and different groups would choose to number at different points in the track, but with both insertions leading to an additional leucine. The latter dbSNP entry includes minor allele frequency data from general populations samples in the Coriell repository with 2/24 African Americans being homozygotes for the insertion and 9/24 African American and 4/23 European individuals noted as heterozygotes. Chen et al (2005) reported allele frequencies for the L9, L10, and L11 variants in the Lipoprotein Coronary Atherosclerosis Study population (LCAS). The sample consistent of 372 35-75yo individuals with LDL-C levels of 115 to 190 mg/dL despite diet and one more coronary lesions of 30-75% stenosis.. Given this selection criteria this cannot be considered a general population sample, however their LDL levels indicate they likely did not have familial hypercholesterolemia. 90/372 individuals studied were heterozygotes for the L10 variant. Yue et al (2006) reported that in a general population sample with normal cholesterol phenotypes 101/403 individuals were heterozygoes for the L10 allele and 9/403 were homozygous. Unfortunately the NHLBI Exome Sequencing Project dataset only reports single nucleotide variation so no data is provided on this variant. Yue et al (2006) found that the variant is associated with lower LDL-C in a Caucasian sample with normal cholesterol. Individuals who had one 9 repeat copy and one 10 repeat copy (i.e. heterozygotes for this variant) had LDL-C that was 10-15 mg/dL lower. They found the 10 repeat variant was an independent predictor of LDL-C. Pisciotta et al (2011) compared total cholesterol LDL-C levels in familial hypercholesterolemia patients who were heterozygous for the 10 repeat variant with those who were homozygous for the wildtype 9 repeat variant and found no differences. However, in the subgroup of individuals treated with statins, the reduction in both total cholesterol and LDL-C was greater in heterozygotes for L10 than in wildtype homozygotes. -

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PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1 Benign:4

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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 07, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

MAF = 9% in 100 subjects with average plasma cholesterol -

Mar 01, 2016

Iberoamerican FH Network

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:4

Nov 15, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29562810, 30782561, 26687699, 25239117, 23743349, 16619215, 23663650, 20006333) -

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia Benign:3

Feb 09, 2023

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 21, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, autosomal dominant, 3 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 14, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.25
Mutation Taster		=81/19	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs35574083; hg19: chr1-55505552; COSMIC: COSV56160392;