1-55039940-G-T

Position:

chr1-55039940-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BS2_Supporting

The ENST00000302118.5(PCSK9):c.103G>T(p.Asp35Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000572 in 1,573,692 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. D35D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

PCSK9
ENST00000302118.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 0.883

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP5

Variant 1-55039940-G-T is Pathogenic according to our data. Variant chr1-55039940-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 375848.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=2, Uncertain_significance=3}.

BS2

High AC in GnomAdExome4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.103G>T	p.Asp35Tyr	missense_variant	1/12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.103G>T	p.Asp35Tyr	missense_variant	1/12	1	NM_174936.4	ENSP00000303208	P2	Q8NBP7-1
PCSK9	ENST00000710286.1 linkuse as main transcript	c.460G>T	p.Asp154Tyr	missense_variant	1/12			ENSP00000518176	A2
PCSK9	ENST00000673913.2 linkuse as main transcript	c.103G>T	p.Asp35Tyr	missense_variant, NMD_transcript_variant	1/12			ENSP00000501161
PCSK9	ENST00000673726.1 linkuse as main transcript	c.103G>T	p.Asp35Tyr	missense_variant, NMD_transcript_variant	1/6			ENSP00000501004

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000108

AC:

AN:

185654

Hom.:

AF XY:

0.00

AC XY:

AN XY:

99494

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000409

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000563

AC:

AN:

1421408

Hom.:

Cov.:

AF XY:

0.00000569

AC XY:

AN XY:

703200

show subpopulations

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:

0.0000247

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000458

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000839

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Pathogenic:3Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces aspartic acid with tyrosine at codon 35 of the PCSK9 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional study has shown that the mutant protein causes slightly higher reduction in LDLR on cell surface by creating a novel Tyr-sulfation site that may enhance the intracellular activity of PCSK9 (PMID: 22683120). Another high-throughput functional study using transfected HEK293 cells has shown that this variant does not impact PCSK9 processing (PMID: 29259136). This variant has been reported in two related individuals affected with familial hypercholesterolemia in one family (PMID: 22683120), and additionally in two unrelated individuals affected with familial hypercholesterolemia (PMID: 29127338; ClinVar SCV002246507.1). It has also been reported in one individual affected with hyperlipidemia (PMID: 33303402). This variant has been identified in 2/185654 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1, family member = 1 / functionnal testing (PMID:22683120) / Software predictions: Conflicting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 35 of the PCSK9 protein (p.Asp35Tyr). This variant is present in population databases (rs764603059, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 22683120, 29127338; Invitae). ClinVar contains an entry for this variant (Variation ID: 375848). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 22683120). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -

PCSK9-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2023

The PCSK9 c.103G>T variant is predicted to result in the amino acid substitution p.Asp35Tyr. This variant has been reported in multiple individuals with hypercholesterolemia (Abifadel et al. 2012. PubMed ID: 22683120; Di Taranto et al. 2017. PubMed ID: 29127338; Chorba et al. 2017. PubMed ID: 29259136. Table S2). Functional study showed that this variant alters PCSK9 function (Abifadel et al. 2012. PubMed ID: 22683120). This variant is reported in 0.0041% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-55505613-G-T). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2023

Published functional studies demonstrate a damaging gain-of-function effect (Abifadel et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 33303402, 29127338, 29038906, 22683120) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2019

The p.D35Y variant (also known as c.103G>T), located in coding exon 1 of the PCSK9 gene, results from a G to T substitution at nucleotide position 103. The aspartic acid at codon 35 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in two related individuals with hypercholesterolemia (Abifadel M et al. Atherosclerosis, 2012 Aug;223:394-400). Functional studies suggest that this alteration creates a new tyrosine sulfation site similar to the nearby Y38 sulfation site, but the physiological relevance of this is unclear (Abifadel M et al. Atherosclerosis, 2012 Aug;223:394-400). 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. -

Familial hypercholesterolemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 29, 2023

This missense variant replaces aspartic acid with tyrosine at codon 35 of the PCSK9 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional study has shown that the mutant protein causes slightly higher reduction in LDLR on cell surface by creating a novel Tyr-sulfation site that may enhance the intracellular activity of PCSK9 (PMID: 22683120). Another high-throughput functional study using transfected HEK293 cells has shown that this variant does not impact PCSK9 processing (PMID: 29259136). This variant has been reported in two related individuals affected with familial hypercholesterolemia in one family (PMID: 22683120), and additionally in two unrelated individuals affected with familial hypercholesterolemia (PMID: 29127338; ClinVar SCV002246507.1). It has also been reported in one individual affected with hyperlipidemia (PMID: 33303402). This variant has been identified in 2/185654 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

0.12

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.62

M_CAP

Uncertain

0.085

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.040

REVEL

Uncertain

0.32

Sift

Uncertain

0.0030

Sift4G

Benign

1.0

Polyphen

0.061

Vest4

0.74

MutPred

0.28

Gain of phosphorylation at D35 (P = 0.0099);

MVP

0.80

MPC

0.90

ClinPred

0.54

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over