NM_000527.5(LDLR):c.949G>A (p.Glu317Lys) AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: May 30, 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:: RCV000237913.13

Allele description [Variation Report for NM_000527.5(LDLR):c.949G>A (p.Glu317Lys)]

NM_000527.5(LDLR):c.949G>A (p.Glu317Lys)

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.949G>A (p.Glu317Lys)

HGVS:

NC_000019.10:g.11110660G>A
NG_009060.1:g.26280G>A
NM_000527.5:c.949G>AMANE SELECT
NM_001195798.2:c.949G>A
NM_001195799.2:c.826G>A
NM_001195800.2:c.445G>A
NM_001195803.2:c.568G>A
NP_000518.1:p.Glu317Lys
NP_000518.1:p.Glu317Lys
NP_001182727.1:p.Glu317Lys
NP_001182728.1:p.Glu276Lys
NP_001182729.1:p.Glu149Lys
NP_001182732.1:p.Glu190Lys
LRG_274t1:c.949G>A
LRG_274:g.26280G>A
NC_000019.9:g.11221336G>A
NM_000527.4(LDLR):c.949G>A
NM_000527.4:c.949G>A
c.949G>A
p.Glu317Lys

Protein change:

E149K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000149; dbSNP: rs746834464

NCBI 1000 Genomes Browser:

rs746834464

Molecular consequence:

NM_000527.5:c.949G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.949G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.826G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.445G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.568G>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

Recent activity

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hypothetical protein (Protein of unknown function, DUF538) [Arabidopsis thaliana...
hypothetical protein (Protein of unknown function, DUF538) [Arabidopsis thaliana]
gi|15220641|ref|NP_174295.1|

Protein
AQ477_RS01030 [Burkholderia thailandensis]
AQ477_RS01030 [Burkholderia thailandensis]
Gene ID:66545491

Gene
nej nejire [Drosophila melanogaster]
nej nejire [Drosophila melanogaster]
Gene ID:43856

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295106	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,
SCV000583768	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000606284	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV001422634	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 23, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 20145306, 25741868 Citation Link,
SCV003807681	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 26, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820238	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (May 30, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 20145306, 32522009, 33418990, 35910211, 36499307, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	4	1	not provided	2	not provided	clinical testing, literature only
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing, research, curation

Citations

PubMed

Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.

Chmara M, Wasag B, Zuk M, Kubalska J, Wegrzyn A, Bednarska-Makaruk M, Pronicka E, Wehr H, Defesche JC, Rynkiewicz A, Limon J.

J Appl Genet. 2010;51(1):95-106. doi: 10.1007/BF03195716.

PubMed [citation]

PMID:: 20145306

Familial Hypercholesterolemia in a Healthy Elderly Population.

Lacaze P, Sebra R, Riaz M, Hooper AJ, Tiller J, Bakshi A, Woods RL, Tonkin AM, Reid CM, Murray AM, Nicholls SJ, Watts GF, Schadt E, McNeil JJ.

Circ Genom Precis Med. 2020 Aug;13(4):e002938. doi: 10.1161/CIRCGEN.120.002938. Epub 2020 Jun 10. No abstract available.

PubMed [citation]

PMID:: 32522009
PMCID:: PMC7442644

See all PubMed Citations (6)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295106.2

#	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 U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583768.1

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

Description

Dutch Lipid Clinic Scoring : Probable FH

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	1	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606284.1

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422634.2

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

Description

The p.Glu317Lys variant in LDLR has been reported in at least 2 individuals (including 1 Polish and 1 Dutch individuals) with Familial Hypercholesterolemia (PMID: 20145306) and 2 individuals with probable Familial Hypercholesterolemia (Variation ID: 251567), and has been identified in 0.02940% (9/30610) of South Asian chromosomes and 0.004010% (1/24936) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs746834464). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 251567). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region (a ligand binding repeat) as p.Glu317Lys have been reported in association with disease in ClinVar and the literature, suggesting that this variant is in a mutational hot spot with functional importance and supports pathogenicity (PMID: 20145306; Variation ID: 251566, 183103, 251570, 251572, 251571). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM1, PP3, PS4_Supporting (Richards 2015).

#	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 Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807681.1

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

Description

ACMG classification criteria: PS4 supporting, PM2 moderated, PP3 supporting

#	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 All of Us Research Program, National Institutes of Health, SCV004820238.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant (also known as p.Glu296Lys in the mature protein) replaces glutamic acid with lysine at codon 317 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 variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 20145306, 33418990, 36499307; ClinVar SCV000583768.1 and SCV003807681.1). It has also been reported in individuals clinically unaffected with hypercholesterolemia (PMID: 32522009, 35910211). This variant has been identified in 15/282452 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		3	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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