NM_174936.4:c.103G>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_174936.4(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
NM_174936.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.883

Publications

11 publications found

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 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

PCSK9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 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 VariationId is 375848.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.103G>T	p.Asp35Tyr	missense_variant	Exon 1 of 12	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.103G>T	p.Asp35Tyr	missense_variant	Exon 1 of 12	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

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

GnomAD2 exomes

AF:

0.0000108

AC:

AN:

185654

AF XY:

0.00

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 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

African (AFR)

AF:

0.00

AC:

AN:

32642

American (AMR)

AF:

0.00

AC:

AN:

38572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25434

East Asian (EAS)

AF:

0.00

AC:

AN:

37498

South Asian (SAS)

AF:

0.0000247

AC:

AN:

80816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49814

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4892

European-Non Finnish (NFE)

AF:

0.00000458

AC:

AN:

1092796

Other (OTH)

AF:

0.0000170

AC:

AN:

58944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74400

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41478

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68056

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000289

Hom.:

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

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

subject mutated among 2600 FH index cases screened = 1, family member = 1 / functionnal testing (PMID:22683120) / Software predictions: Conflicting -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 24, 2021

Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PCSK9-related disorder

Pathogenic:1

Mar 25, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 05, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 27, 2019

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Mar 24, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces aspartic acid with tyrosine at codon 35 of the PCSK9 protein. Computational prediction suggests that this variant may not impact 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 an 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

(source)

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

PhyloP100

0.88

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

PromoterAI

-0.046

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.72

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over