NM_174936.4(PCSK9):c.212C>T (p.Pro71Leu) AND Hypercholesterolemia, autosomal dominant, 3

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 8, 2024
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:: RCV000539746.11

Allele description [Variation Report for NM_174936.4(PCSK9):c.212C>T (p.Pro71Leu)]

NM_174936.4(PCSK9):c.212C>T (p.Pro71Leu)

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.212C>T (p.Pro71Leu)

HGVS:

NC_000001.11:g.55043847C>T
NG_009061.1:g.9301C>T
NM_174936.4:c.212C>TMANE SELECT
NP_777596.2:p.Pro71Leu
NP_777596.2:p.Pro71Leu
LRG_275t1:c.212C>T
LRG_275:g.9301C>T
LRG_275p1:p.Pro71Leu
NC_000001.10:g.55509520C>T
NM_174936.3:c.212C>T

Protein change:

P71L

Links:

dbSNP: rs569379713

NCBI 1000 Genomes Browser:

rs569379713

Molecular consequence:

NM_174936.4:c.212C>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000644869	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 8, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003925117	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (May 11, 2022)	germline	clinical testing	Citation Link,
SCV004844088	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26374825, 34526433, 36499307, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000644869

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Jan 8, 2024)

germline

clinical testing

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

SCV003925117

New York Genome Center

criteria provided, single submitter

(NYGC Assertion Criteria 2020)

Uncertain significance
(May 11, 2022)

germline

clinical testing

Citation Link,

SCV004844088

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	6	not provided	not provided	108545	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody.

Hopkins PN, Defesche J, Fouchier SW, Bruckert E, Luc G, Cariou B, Sjouke B, Leren TP, Harada-Shiba M, Mabuchi H, Rabès JP, Carrié A, van Heyningen C, Carreau V, Farnier M, Teoh YP, Bourbon M, Kawashiri MA, Nohara A, Soran H, Marais AD, Tada H, et al.

Circ Cardiovasc Genet. 2015 Dec;8(6):823-31. doi: 10.1161/CIRCGENETICS.115.001129. Epub 2015 Sep 15.

PubMed [citation]

PMID:: 26374825
PMCID:: PMC5098466

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000644869.4

#	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 New York Genome Center, SCV003925117.1

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

Description

The c.212C>T variant in PCSK9 has previously been reported in individuals with clinical features of familial hypercholesterolemia, coronary artery disease (CAD) and stroke [PMID: 26374825, 27920219, 34526433] and it has been deposited in ClinVar [ClinVar ID: 440711] as a Variant of Uncertain Significance. The c.212C>T variant is observed in 34 alleles (0.0063 % minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.212C>T variant in PCSK9 is located in exon 2 of this 12-exon gene and is predicted to replace a weakly conserved proline amino acid with leucine at position 71 of this 692-amino-acid protein. In silico tools predict the p.(Pro71Leu) variant tobe benign [(CADD v1.6 = 15.72, REVEL = 0.079)]; however, there are no functional studies to support or refute these predictions. Based on the available evidence, the c.212C>T p.(Pro71Leu) missense variant identified in the PCSK9 gene is reported 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	1	not provided	not provided		1	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004844088.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces proline with leucine at codon 71 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 26374825, 36499307) and in an individual affected with acute coronary syndrome (PMID: 34526433). This variant has been identified in 27/250360 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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