NM_000527.5(LDLR):c.669G>C (p.Lys223Asn) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 16, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003741172.2

Allele description [Variation Report for NM_000527.5(LDLR):c.669G>C (p.Lys223Asn)]

NM_000527.5(LDLR):c.669G>C (p.Lys223Asn)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.669G>C (p.Lys223Asn)

HGVS:

NC_000019.10:g.11105575G>C
NG_009060.1:g.21195G>C
NM_000527.5:c.669G>CMANE SELECT
NM_001195798.2:c.669G>C
NM_001195799.2:c.546G>C
NM_001195800.2:c.314-1817G>C
NM_001195803.2:c.314-990G>C
NP_000518.1:p.Lys223Asn
NP_000518.1:p.Lys223Asn
NP_001182727.1:p.Lys223Asn
NP_001182728.1:p.Lys182Asn
LRG_274t1:c.669G>C
LRG_274:g.21195G>C
LRG_274p1:p.Lys223Asn
NC_000019.9:g.11216251G>C
NM_000527.4:c.669G>C
c.669G>C

Protein change:

K182N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001799; dbSNP: rs879254627

NCBI 1000 Genomes Browser:

rs879254627

Molecular consequence:

NM_001195800.2:c.314-1817G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-990G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.669G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.669G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.546G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004538264	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20809525, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004538264

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 16, 2023)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004538264.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251370). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 223 of the LDLR protein (p.Lys223Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525).

#	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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