1-55039879-ACTGCTGCTG-ACTGCTGCTGCTGCTG

Variant names:

• chr1-55039879-A-ACTGCTG
• rs35574083
• NM_174936.4:c.60_65dupGCTGCT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_174936.4(PCSK9):​c.60_65dupGCTGCT​(p.Leu21_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 0.00321 in 1,557,940 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L22L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (8 hom.)
• Consequence: PCSK9 NM_174936.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -0.246

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 1-55039879-A-ACTGCTG is Benign according to our data. Variant chr1-55039879-A-ACTGCTG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265916.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=5, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00269 (409/152186) while in subpopulation AMR AF= 0.00366 (56/15300). AF 95% confidence interval is 0.00289. There are 1 homozygotes in gnomad4. There are 190 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 409 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.60_65dupGCTGCT	p.Leu21_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.60_65dupGCTGCT	p.Leu21_Leu22dup	disruptive_inframe_insertion	Exon 1 of 12	1	NM_174936.4	ENSP00000303208.5
PCSK9	ENST00000710286.1	c.417_422dupGCTGCT	p.Leu140_Leu141dup	disruptive_inframe_insertion	Exon 1 of 12			ENSP00000518176.1
PCSK9	ENST00000673726.1	n.60_65dupGCTGCT		non_coding_transcript_exon_variant	Exon 1 of 6			ENSP00000501004.1
PCSK9	ENST00000673913.2	n.60_65dupGCTGCT		non_coding_transcript_exon_variant	Exon 1 of 12			ENSP00000501161.2

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 407 AN: 152070 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00277 AC: 446 AN: 161082 Hom.: 1 AF XY: 0.00272 AC XY: 235 AN XY: 86248

Gnomad AFR exome AF: 0.000115

Gnomad AMR exome AF: 0.00268

Gnomad ASJ exome AF: 0.00734

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000822

Gnomad FIN exome AF: 0.00401

Gnomad NFE exome AF: 0.00329

Gnomad OTH exome AF: 0.00557

GnomAD4 exome AF: 0.00327 AC: 4595 AN: 1405754 Hom.: 8 Cov.: 30 AF XY: 0.00320 AC XY: 2220 AN XY: 694300

Gnomad4 AFR exome AF: 0.000622

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00831

Gnomad4 EAS exome AF: 0.0000542

Gnomad4 SAS exome AF: 0.000902

Gnomad4 FIN exome AF: 0.00405

Gnomad4 NFE exome AF: 0.00347

Gnomad4 OTH exome AF: 0.00360

GnomAD4 genome AF: 0.00269 AC: 409 AN: 152186 Hom.: 1 Cov.: 31 AF XY: 0.00255 AC XY: 190 AN XY: 74422

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.00324

Gnomad4 OTH AF: 0.00427

Bravo AF: 0.00283

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1 Benign:3

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

0/100 French Canadian and 0/100 French normolipidemic and trigliceridemic controls; 0/100 Tunisian normolipidemic individuals -

Jul 07, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 02, 2018

Robarts Research Institute, Western University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCSK9: BS1, BS2 -

Oct 12, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PCSK9 c.60_65dupGCTGCT (p.Leu20_Leu21dup) variant involves the duplication of 6 nucleotides in a Leucine repeat region, changing 9 Leucines to 11 Leucines. Mutation taster predicts a benign outcome for this variant. This variant was found in 49/22348 control chromosomes (1 homozygote) at a frequency of 0.0021926, which is approximately 23 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.0000938), suggesting this variant is likely a benign polymorphism. This variant has been reported in families with FH and FCHL but did not clearly cosegregate with disease. Additionally, the variant has been reported in patients that carry other pathogenic variants which would suggest that this is a benign variant. Taken together, this variant is classified as benign. -

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Feb 05, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 05, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu22_Leu23dup variant in PCSK9 is classified as benign because it has been identified in 0.74% (65/8730) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jul 30, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial hypercholesterolemia Benign:1

Jun 29, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35574083; hg19: chr1-55505552;