NM_000527.5(LDLR):c.1057G>A (p.Glu353Lys) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Jan 11, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000237927.16

Allele description [Variation Report for NM_000527.5(LDLR):c.1057G>A (p.Glu353Lys)]

NM_000527.5(LDLR):c.1057G>A (p.Glu353Lys)

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.1057G>A (p.Glu353Lys)

HGVS:

NC_000019.10:g.11110768G>A
NG_009060.1:g.26388G>A
NM_000527.5:c.1057G>AMANE SELECT
NM_001195798.2:c.1057G>A
NM_001195799.2:c.934G>A
NM_001195800.2:c.553G>A
NM_001195803.2:c.676G>A
NP_000518.1:p.Glu353Lys
NP_000518.1:p.Glu353Lys
NP_001182727.1:p.Glu353Lys
NP_001182728.1:p.Glu312Lys
NP_001182729.1:p.Glu185Lys
NP_001182732.1:p.Glu226Lys
LRG_274t1:c.1057G>A
LRG_274:g.26388G>A
LRG_274p1:p.Glu353Lys
NC_000019.9:g.11221444G>A
NM_000527.4:c.1057G>A
c.1057G>A

Protein change:

E185K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000791;

Molecular consequence:

NM_000527.5:c.1057G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1057G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.934G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.676G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

unknown functional consequence - Comment(s)

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

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
SCV000295172	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Uncertain significance (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 11810272, 15823288 Citation Link,
SCV000588545	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000606304	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV002784200	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 21, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820261	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11810272, 15823288, 20506408, 30971288, 25741868

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	9	not provided	not provided	108544	not provided	clinical testing, research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]

PMID:: 11810272

The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population.

Damgaard D, Larsen ML, Nissen PH, Jensen JM, Jensen HK, Soerensen VR, Jensen LG, Faergeman O.

Atherosclerosis. 2005 May;180(1):155-60. Epub 2005 Jan 12.

PubMed [citation]

PMID:: 15823288

See all PubMed Citations (5)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295172.2

#	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 Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588545.1

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

Description

%MAF(ExAC):0.007442

#	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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606304.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002784200.1

#	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	unknown	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, SCV004820261.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant (also known as p.Glu332Lys in the mature protein) replaces glutamic acid with lysine at codon 353 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 20506408; Huang et al, 2021, doi.org/10.5551/jat.62773), as well as in an individual affected with premature myocardial infarction (PMID: 30971288). This variant has also been identified in 16/281978 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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		9	not provided	not provided	not provided

Last Updated: Oct 26, 2024

ClinVar

Relating variation to medicine