NM_000527.5(LDLR):c.352G>A (p.Asp118Asn) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 15, 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:: RCV001273281.15

Allele description [Variation Report for NM_000527.5(LDLR):c.352G>A (p.Asp118Asn)]

NM_000527.5(LDLR):c.352G>A (p.Asp118Asn)

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.352G>A (p.Asp118Asn)

HGVS:

NC_000019.10:g.11105258G>A
NG_009060.1:g.20878G>A
NM_000527.5:c.352G>AMANE SELECT
NM_001195798.2:c.352G>A
NM_001195799.2:c.229G>A
NM_001195800.2:c.314-2134G>A
NM_001195803.2:c.314-1307G>A
NP_000518.1:p.Asp118Asn
NP_000518.1:p.Asp118Asn
NP_001182727.1:p.Asp118Asn
NP_001182728.1:p.Asp77Asn
LRG_274t1:c.352G>A
LRG_274:g.20878G>A
LRG_274p1:p.Asp118Asn
NC_000019.9:g.11215934G>A
NM_000527.4:c.352G>A

Protein change:

D118N

Links:

dbSNP: rs730882080

NCBI 1000 Genomes Browser:

rs730882080

Molecular consequence:

NM_001195800.2:c.314-2134G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1307G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.352G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.352G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.229G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000285030	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 15, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 32715071, 36229376, 11317362, 17196209, 20045108, 23375686, 28492532
SCV001456141	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000285030

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 15, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001456141

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 16, 2020)

germline

clinical testing

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

Xanthomas heralding pediatric coronary artery disease.

Edelman A, Wetzel M, Owen C, Schadt CR, Callen JP.

JAAD Case Rep. 2020 Aug;6(8):753-754. doi: 10.1016/j.jdcr.2020.06.010. No abstract available.

PubMed [citation]

PMID:: 32715071
PMCID:: PMC7369508

Impact of variants of uncertain significance of LDL receptor on phenotypes of familial hypercholesterolemia.

Tada H, Kojima N, Yamagami K, Nomura A, Nohara A, Usui S, Sakata K, Hayashi K, Fujino N, Takamura M, Kawashiri MA.

J Clin Lipidol. 2022 Nov-Dec;16(6):863-869. doi: 10.1016/j.jacl.2022.09.007. Epub 2022 Sep 30.

PubMed [citation]

PMID:: 36229376

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000285030.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 118 of the LDLR protein (p.Asp118Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 32715071, 36229376; Invitae). ClinVar contains an entry for this variant (Variation ID: 237873). 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 not expected to disrupt LDLR protein function with a negative predictive value of 95%. This variant disrupts the p.Asp118 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11317362, 17196209, 20045108, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Natera, Inc., SCV001456141.1

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

#	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: Nov 3, 2024

ClinVar

Relating variation to medicine