NM_174936.4(PCSK9):c.835C>A (p.Pro279Thr) AND Hypercholesterolemia, autosomal dominant, 3

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 25, 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:: RCV000417269.16

Allele description [Variation Report for NM_174936.4(PCSK9):c.835C>A (p.Pro279Thr)]

NM_174936.4(PCSK9):c.835C>A (p.Pro279Thr)

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.835C>A (p.Pro279Thr)

HGVS:

NC_000001.11:g.55056028C>A
NG_009061.1:g.21482C>A
NM_001407240.1:c.958C>A
NM_001407241.1:c.835C>A
NM_001407242.1:c.838C>A
NM_001407243.1:c.778C>A
NM_001407244.1:c.835C>A
NM_001407245.1:c.643C>A
NM_001407246.1:c.460C>A
NM_001407247.1:c.835C>A
NM_174936.4:c.835C>AMANE SELECT
NP_001394169.1:p.Pro320Thr
NP_001394170.1:p.Pro279Thr
NP_001394171.1:p.Pro280Thr
NP_001394172.1:p.Pro260Thr
NP_001394173.1:p.Pro279Thr
NP_001394174.1:p.Pro215Thr
NP_001394175.1:p.Pro154Thr
NP_001394176.1:p.Pro279Thr
NP_777596.2:p.Pro279Thr
NP_777596.2:p.Pro279Thr
LRG_275t1:c.835C>A
LRG_275:g.21482C>A
LRG_275p1:p.Pro279Thr
NC_000001.10:g.55521701C>A
NM_174936.3:c.835C>A
NR_110451.2:n.494C>A
NR_110451.3:n.1168C>A
NR_176318.1:n.809C>A
NR_176319.1:n.1125C>A
NR_176320.1:n.1248C>A
NR_176321.1:n.1125C>A
NR_176322.1:n.1125C>A
NR_176323.1:n.1125C>A
NR_176324.1:n.1387C>A

Protein change:

P154T

Links:

dbSNP: rs72646509

NCBI 1000 Genomes Browser:

rs72646509

Molecular consequence:

NM_001407240.1:c.958C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407241.1:c.835C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407242.1:c.838C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407243.1:c.778C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407244.1:c.835C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407245.1:c.643C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407246.1:c.460C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407247.1:c.835C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_174936.4:c.835C>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000503507	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000644874	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 25, 2024)	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

SCV000503507

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 16, 2016)

germline

clinical testing

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

SCV000644874

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Jan 25, 2024)

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	yes	not provided	not provided	not provided	2600	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

Details of each submission

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503507.1

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

Description

subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000644874.8

#	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

Last Updated: Sep 29, 2024

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