NM_174936.4(PCSK9):c.316G>A (p.Gly106Arg) AND Hypercholesterolemia, autosomal dominant, 3

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 2, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001782586.11

Allele description [Variation Report for NM_174936.4(PCSK9):c.316G>A (p.Gly106Arg)]

NM_174936.4(PCSK9):c.316G>A (p.Gly106Arg)

Gene:

PCSK9:proprotein convertase subtilisin/kexin type 9 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p32.3

Genomic location:

Preferred name:

NM_174936.4(PCSK9):c.316G>A (p.Gly106Arg)

HGVS:

NC_000001.11:g.55043951G>A
NG_009061.1:g.9405G>A
NM_174936.4:c.316G>AMANE SELECT
NP_777596.2:p.Gly106Arg
LRG_275:g.9405G>A
NC_000001.10:g.55509624G>A

Protein change:

G106R

Links:

dbSNP: rs2100267180

NCBI 1000 Genomes Browser:

rs2100267180

Molecular consequence:

NM_174936.4:c.316G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypercholesterolemia, autosomal dominant, 3 (FHCL3)
Synonyms:: Familial hypercholesterolemia 3; Familial Hypercholesterolemia, Autosomal Dominant, 3
Identifiers:: MONDO: MONDO:0011369; MedGen: C1863551; OMIM: 603776

Recent activity

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Salmonella enterica subsp. enterica serovar Typhimurium strain N029 N029_trimmed...
Salmonella enterica subsp. enterica serovar Typhimurium strain N029 N029_trimmed_contig_185, whole genome shotgun sequence
gi|1279956601|gb|PHGX01000184.1||gn :PHGX01|N029_trimmed_contig_185

Nucleotide
Salmonella enterica subsp. enterica serovar Typhimurium strain N029 N029_trimmed...
Salmonella enterica subsp. enterica serovar Typhimurium strain N029 N029_trimmed_contig_107, whole genome shotgun sequence
gi|1279957056|gb|PHGX01000107.1||gn :PHGX01|N029_trimmed_contig_107

Nucleotide
Salmonella enterica subsp. enterica serovar Typhimurium strain N029 N029_trimmed...
Salmonella enterica subsp. enterica serovar Typhimurium strain N029 N029_trimmed_contig_131, whole genome shotgun sequence
gi|1279956779|gb|PHGX01000131.1||gn :PHGX01|N029_trimmed_contig_131

Nucleotide
Salmonella enterica subsp. enterica serovar Typhimurium strain N029 N029_trimmed...
Salmonella enterica subsp. enterica serovar Typhimurium strain N029 N029_trimmed_contig_126, whole genome shotgun sequence
gi|1279956794|gb|PHGX01000126.1||gn :PHGX01|N029_trimmed_contig_126

Nucleotide
Limosilactobacillus reuteri strain 107e 107e_8, whole genome shotgun sequence
Limosilactobacillus reuteri strain 107e 107e_8, whole genome shotgun sequence
gi|1231622912|gb|NGPT01000008.1||gn :NGPT01|107e_8

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002021640	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002220029	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 7, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16424354, 18266662, 18710658, 16571601, 28492532
SCV004841148	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Benign (Oct 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002021640

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 6, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002220029

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 7, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004841148

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Benign
(Oct 2, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy.

Berge KE, Ose L, Leren TP.

Arterioscler Thromb Vasc Biol. 2006 May;26(5):1094-100. Epub 2006 Jan 19.

PubMed [citation]

PMID:: 16424354

Characterization of novel mutations in the catalytic domain of the PCSK9 gene.

Cameron J, Holla OL, Laerdahl JK, Kulseth MA, Ranheim T, Rognes T, Berge KE, Leren TP.

J Intern Med. 2008 Apr;263(4):420-31. doi: 10.1111/j.1365-2796.2007.01915.x. Epub 2008 Feb 2.

PubMed [citation]

PMID:: 18266662

See all PubMed Citations (6)

Details of each submission

From Revvity Omics, Revvity, SCV002021640.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002220029.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glycine with arginine at codon 106 of the PCSK9 protein (p.Gly106Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with hypocholesterolemia (PMID: 16424354, 18266662, 18710658). 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: 16571601). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004841148.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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