NM_000527.5(LDLR):c.1066G>A (p.Asp356Asn) AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Nov 20, 2023
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:: RCV000238202.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1066G>A (p.Asp356Asn)]

NM_000527.5(LDLR):c.1066G>A (p.Asp356Asn)

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.1066G>A (p.Asp356Asn)

HGVS:

NC_000019.10:g.11111519G>A
NG_009060.1:g.27139G>A
NM_000527.5:c.1066G>AMANE SELECT
NM_001195798.2:c.1066G>A
NM_001195799.2:c.943G>A
NM_001195800.2:c.562G>A
NM_001195803.2:c.685G>A
NP_000518.1:p.Asp356Asn
NP_000518.1:p.Asp356Asn
NP_001182727.1:p.Asp356Asn
NP_001182728.1:p.Asp315Asn
NP_001182729.1:p.Asp188Asn
NP_001182732.1:p.Asp229Asn
LRG_274t1:c.1066G>A
LRG_274:g.27139G>A
LRG_274p1:p.Asp356Asn
NC_000019.9:g.11222195G>A
NM_000527.4:c.1066G>A
c.1066G>A

Protein change:

D188N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000157; dbSNP: rs767767730

NCBI 1000 Genomes Browser:

rs767767730

Molecular consequence:

NM_000527.5:c.1066G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1066G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.943G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.562G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.685G>A - 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
SCV000295195	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely benign (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 15998910, 20145306 Citation Link,
SCV000606315	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV004820262	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 20, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9104431, 11851376, 15256764, 15998910, 19319977, 20145306, 20809525, 32977124, 35929461, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295195

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely benign
(Mar 25, 2016)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000606315

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

no assertion criteria provided

Pathogenic

germline

research

SCV004820262

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 20, 2023)

germline

clinical testing

PubMed (10)
[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	2	not provided	not provided	2	not provided	literature only
not provided	germline	unknown	6	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Molecular genetics of familial hypercholesterolaemia in Norway.

Leren TP, Tonstad S, Gundersen KE, Bakken KS, Rødningen OK, Sundvold H, Ose L, Berg K.

J Intern Med. 1997 Mar;241(3):185-94.

PubMed [citation]

PMID:: 9104431

Low-density lipoprotein receptor gene mutation analysis and clinical correlation in Belgian hypercholesterolaemics.

Van Gaal LF, Peeters AV, De Block CE, de Leeuw IH, Thiart R, Kotze MJ.

Mol Cell Probes. 2001 Dec;15(6):329-36.

PubMed [citation]

PMID:: 11851376

See all PubMed Citations (10)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295195.2

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

#	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
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606315.1

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

From All of Us Research Program, National Institutes of Health, SCV004820262.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (10)

Description

This missense variant (also known as p.Asp335Asn in the mature protein) replaces aspartic acid with asparagine at codon 356 of the LDLR 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: 15998910, 20145306). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 32977124). This variant has been identified in 3/251248 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Three, rare missense variants occurring at the same codon (p.Asp356His, p.Asp356Tyr, p.Asp356Ala) have been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 9104431, 11851376, 15256764, 19319977, 20145306, 20809525, 35929461), indicating that aspartic acid 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		6	not provided	not provided	not provided

Last Updated: May 7, 2024

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