NM_000527.5(LDLR):c.2146G>A (p.Glu716Lys) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 19, 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:: RCV003581644.1

Allele description [Variation Report for NM_000527.5(LDLR):c.2146G>A (p.Glu716Lys)]

NM_000527.5(LDLR):c.2146G>A (p.Glu716Lys)

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.2146G>A (p.Glu716Lys)

HGVS:

NC_000019.10:g.11123179G>A
NG_009060.1:g.38799G>A
NM_000527.5:c.2146G>AMANE SELECT
NM_001195798.2:c.2146G>A
NM_001195799.2:c.2023G>A
NM_001195800.2:c.1642G>A
NM_001195803.2:c.1612G>A
NP_000518.1:p.Glu716Lys
NP_000518.1:p.Glu716Lys
NP_001182727.1:p.Glu716Lys
NP_001182728.1:p.Glu675Lys
NP_001182729.1:p.Glu548Lys
NP_001182732.1:p.Glu538Lys
LRG_274t1:c.2146G>A
LRG_274:g.38799G>A
LRG_274p1:p.Glu716Lys
NC_000019.9:g.11233855G>A
NM_000527.4:c.2146G>A
c.2146G>A

Protein change:

E538K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000285; dbSNP: rs879255149

NCBI 1000 Genomes Browser:

rs879255149

Molecular consequence:

NM_000527.5:c.2146G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2146G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2023G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1642G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1612G>A - 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
SCV004359060	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20828696, 26020417, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004359060

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 19, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Update of the Portuguese Familial Hypercholesterolaemia Study.

Medeiros AM, Alves AC, Francisco V, Bourbon M; investigators of the Portuguese FH Study.

Atherosclerosis. 2010 Oct;212(2):553-8. doi: 10.1016/j.atherosclerosis.2010.07.012. Epub 2010 Aug 8.

PubMed [citation]

PMID:: 20828696

Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement.

Medeiros AM, Alves AC, Bourbon M.

Genet Med. 2016 Apr;18(4):316-24. doi: 10.1038/gim.2015.71. Epub 2015 May 28.

PubMed [citation]

PMID:: 26020417

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV004359060.1

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

Description

This missense variant (also known as p.Glu695Lys in the mature protein) replaces glutamic acid with lysine at codon 716 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 observed in compound heterozygous state in an individual affected with homozygous familial hypercholesterolemia (PMID: 20828696, 26020417), indicating that this variant contributes to disease. This variant has not been identified 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 19, 2025

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