rs11583680

chr1-55039995-C-Gchr1-55039995-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_174936.4(PCSK9):c.158C>G(p.Ala53Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000507 in 1,578,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A53V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:7
• Conservation: PhyloP100: 1.52

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 uncertain in NM_174936.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.09123236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.158C>G	p.Ala53Gly	missense_variant	1/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.158C>G	p.Ala53Gly	missense_variant	1/12	1	NM_174936.4	P2
PCSK9	ENST00000710286.1	c.515C>G	p.Ala172Gly	missense_variant	1/12			A2
PCSK9	ENST00000673913.2	c.158C>G	p.Ala53Gly	missense_variant, NMD_transcript_variant	1/12
PCSK9	ENST00000673726.1	c.158C>G	p.Ala53Gly	missense_variant, NMD_transcript_variant	1/6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000156 AC: 3 AN: 192322 Hom.: 0 AF XY: 0.0000193 AC XY: 2 AN XY: 103386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000540 AC: 77 AN: 1425882 Hom.: 0 Cov.: 31 AF XY: 0.0000708 AC XY: 50 AN XY: 705878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000392

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000676

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000168 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This missense variant replaces alanine with glycine at codon 53 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in double heterozygous state with a known pathogenic LDLR variant in two related individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious variants (PMID: 27919364). This variant has been identified in 4/223722 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 30, 2021	- -

Hypercholesterolemia, familial, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

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- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 20, 2020

Variant summary: PCSK9 c.158C>G (p.Ala53Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 192322 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.158C>G has been reported in the literature in two individuals affected with Autosomal dominant hypercholesterolemia who also carried another pathogenic variant (LDLR c.1285G>A, p.Val429Met) (Sjouke_2016). The report does not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance -

Hypobetalipoproteinemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The p.A53G variant (also known as c.158C>G), located in coding exon 1 of the PCSK9 gene, results from a C to G substitution at nucleotide position 158. The alanine at codon 53 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in a familial hypercholesterolemia (FH) cohort; however, an additional alteration was detected in an associated gene (Sjouke B et al. J Clin Lipidol Sep;10:1462-1469). Additionally, this alteration was detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 22, 2023

This missense variant replaces alanine with glycine at codon 53 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in double heterozygous state with a known pathogenic LDLR variant in two related individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious variants (PMID: 27919364). This variant has been identified in 4/223722 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.041
Sift	Benign	0.060	T
Sift4G	Benign	0.39	T
Polyphen		0.079	B
Vest4		0.11
MutPred		0.27		Gain of loop (P = 0.0013);
MVP		0.73
MPC		0.24
ClinPred		0.052	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.73

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: rs11583680; hg19: chr1-55505668;