rs886039839

Variant names:

• chr1-55040022-C-A
• rs886039839
• NM_174936.4:c.185C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 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: Uncertain_significance. The variant received 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 submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.185C>A	p.Ala62Asp	missense_variant	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.185C>A	p.Ala62Asp	missense_variant	Exon 1 of 12	1	NM_174936.4	ENSP00000303208.5

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

African (AFR) AF: 0.00 AC: 0 AN: 32528

American (AMR) AF: 0.00 AC: 0 AN: 39448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25410

East Asian (EAS) AF: 0.00 AC: 0 AN: 37284

South Asian (SAS) AF: 0.00 AC: 0 AN: 80688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4562

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1091366

Other (OTH) AF: 0.00 AC: 0 AN: 58762

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

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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

Hypercholesterolemia, autosomal dominant, 3 Uncertain:1

Feb 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). ClinVar contains an entry for this variant (Variation ID: 265918). 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. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 26541928). 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. -

Cardiovascular phenotype Uncertain:1

Jul 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		3.9
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
PromoterAI		-0.0086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.94
Mutation Taster		=31/69	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886039839; hg19: chr1-55505695;