NM_000527.5(LDLR):c.2473A>G (p.Asn825Asp) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Mar 20, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000237741.4

Allele description [Variation Report for NM_000527.5(LDLR):c.2473A>G (p.Asn825Asp)]

NM_000527.5(LDLR):c.2473A>G (p.Asn825Asp)

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.2473A>G (p.Asn825Asp)

Other names:

NM_000527.5(LDLR):c.2473A>G; p.Asn825Asp

HGVS:

NC_000019.10:g.11129596A>G
NG_009060.1:g.45216A>G
NM_000527.5:c.2473A>GMANE SELECT
NM_001195798.2:c.2473A>G
NM_001195799.2:c.2350A>G
NM_001195800.2:c.1969A>G
NM_001195803.2:c.1939A>G
NP_000518.1:p.Asn825Asp
NP_001182727.1:p.Asn825Asp
NP_001182728.1:p.Asn784Asp
NP_001182729.1:p.Asn657Asp
NP_001182732.1:p.Asn647Asp
LRG_274:g.45216A>G
NC_000019.9:g.11240272A>G
c.2473A>G

Protein change:

N647D

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001127; dbSNP: rs879255215

NCBI 1000 Genomes Browser:

rs879255215

Molecular consequence:

NM_000527.5:c.2473A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2473A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2350A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1969A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1939A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000296014	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004022382	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Mar 20, 2023)	germline	curation	Citation Link,
SCV004824286	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15556094, 33418990, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000296014

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

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

Citation Link,

SCV004022382

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Likely pathogenic
(Mar 20, 2023)

germline

curation

Citation Link,

SCV004824286

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 8, 2023)

germline

clinical testing

PubMed (3)
[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	yes	1	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective.

Laurie AD, Scott RS, George PM.

Atheroscler Suppl. 2004 Dec;5(5):13-5.

PubMed [citation]

PMID:: 15556094

The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia.

Meshkov A, Ershova A, Kiseleva A, Zotova E, Sotnikova E, Petukhova A, Zharikova A, Malyshev P, Rozhkova T, Blokhina A, Limonova A, Ramensky V, Divashuk M, Khasanova Z, Bukaeva A, Kurilova O, Skirko O, Pokrovskaya M, Mikova V, Snigir E, Akinshina A, Mitrofanov S, et al.

Genes (Basel). 2021 Jan 6;12(1). doi: 10.3390/genes12010066.

PubMed [citation]

PMID:: 33418990
PMCID:: PMC7825309

See all PubMed Citations (3)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000296014.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (1)

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

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV004022382.1

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

Description

The NM_000527.5 (LDLR):c.2473A>G (p.Asn825Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PM5) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.93. PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil FH diagnostic criteria. One index case fulfil criteria of TC > 8mmol/l and strong family history of CAD, Laurie et al, 2004, Canterbury Health Laboratories, New Zealand, PMID: 15556094. One index case with DLCN score >=6, Meshkov et al, 2021, National Medical Research Center for Therapy and Preventive Medicine, Russia, PMID: 33418990. PM5: Two other missense variants in the same codon: NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys), (ClinVarID 161265), is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys), (ClinVarID 252341), is classified as Pathogenic by these guidelines, therefore PM5 is met.

#	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, SCV004824286.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant (also known as p.Asn804Asp in the mature protein) replaces asparagine with aspartic acid at codon 825 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in one heterozygous individual affected with familial hypercholesterolemia (PMID: 33418990). This variant has also been observed in compound heterozygous state with a different LDLR variant of uncertain significance in an individual affected with severe homozygous familial hypercholesterolemia (PMID: 15556094). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Asn825Lys, is considered to be disease-causing (ClinVar variation ID: 161265), suggesting that asparagine at this position is important for LDLR protein function. 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		1	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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