1-55052408-A-T

Variant names:

• chr1-55052408-A-T
• rs970575319
• NM_174936.4:c.654A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_174936.4(PCSK9):​c.654A>T​(p.Arg218Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R218G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.36
• Publications: 3 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_174936.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-55052406-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1524079.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831
• PP5: Variant 1-55052408-A-T is Pathogenic according to our data. Variant chr1-55052408-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 438334.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174936.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	NM_174936.4	MANE Select	c.654A>T	p.Arg218Ser	missense	Exon 4 of 12	NP_777596.2
	PCSK9	NM_001407240.1		c.777A>T	p.Arg259Ser	missense	Exon 5 of 13	NP_001394169.1	A0AAQ5BGX4
	PCSK9	NM_001407241.1		c.654A>T	p.Arg218Ser	missense	Exon 4 of 12	NP_001394170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.654A>T	p.Arg218Ser	missense	Exon 4 of 12	ENSP00000303208.5	Q8NBP7-1
	PCSK9	ENST00000710286.1		c.1011A>T	p.Arg337Ser	missense	Exon 4 of 12	ENSP00000518176.1	A0AA34QVH0
	PCSK9	ENST00000713786.1		c.777A>T	p.Arg259Ser	missense	Exon 5 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Hypercholesterolemia, autosomal dominant, 3 (1)
-	1	-	Hypercholesterolemia, familial, 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.65	N
PhyloP100		1.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.64
Sift	Benign	0.090	T
Sift4G	Benign	0.10	T
Polyphen		0.58	P
Vest4		0.66
MutPred		0.77		Gain of phosphorylation at R218 (P = 0.0495)
MVP		0.91
MPC		0.69
ClinPred		0.59	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.49
gMVP		0.69
Mutation Taster		=10/90	disease causing

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: rs970575319; hg19: chr1-55518081;