rs886039839

Positions:

• chr1-55040022-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_174936.4(PCSK9):​c.185C>A​(p.Ala62Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,419,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A62A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 3.87

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-55040022-C-A is Pathogenic according to our data. Variant chr1-55040022-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265918.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.185C>A	p.Ala62Asp	missense_variant	1/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.185C>A	p.Ala62Asp	missense_variant	1/12	1	NM_174936.4	P2
PCSK9	ENST00000710286.1	c.542C>A	p.Ala181Asp	missense_variant	1/12			A2
PCSK9	ENST00000673913.2	c.185C>A	p.Ala62Asp	missense_variant, NMD_transcript_variant	1/12
PCSK9	ENST00000673726.1	c.185C>A	p.Ala62Asp	missense_variant, NMD_transcript_variant	1/6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1419926 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 702606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Mar 01, 2016

0/190 non-FH alleles (portuguese normolipidemic individuals) -

Hypercholesterolemia, autosomal dominant, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 20, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 62 of the PCSK9 protein (p.Ala62Asp). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 26541928; Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 26541928). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCSK9 protein function. ClinVar contains an entry for this variant (Variation ID: 265918). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2021

The p.A62D variant (also known as c.185C>A), located in coding exon 1 of the PCSK9 gene, results from a C to A substitution at nucleotide position 185. The alanine at codon 62 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant co-occurred with a second PCSK9 variant in an individual with familial hypercholesterolemia. Functional assays from the same group suggested this variant may lead to reduced LDLR cell surface expression (Alves AC et al. J Am Coll Cardiol, 2015 Nov;66:2152-2154). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.020
Eigen_PC	Benign	-0.0062
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.85	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.93	P
Vest4		0.55
MutPred		0.56		Gain of disorder (P = 0.0766);
MVP		0.83
MPC		0.95
ClinPred		0.85	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.94

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: rs886039839; hg19: chr1-55505695;