NM_000527.5(LDLR):c.1009G>A (p.Glu337Lys) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 7, 2023
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:: RCV000627183.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1009G>A (p.Glu337Lys)]

NM_000527.5(LDLR):c.1009G>A (p.Glu337Lys)

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.1009G>A (p.Glu337Lys)

HGVS:

NC_000019.10:g.11110720G>A
NG_009060.1:g.26340G>A
NM_000527.5:c.1009G>AMANE SELECT
NM_001195798.2:c.1009G>A
NM_001195799.2:c.886G>A
NM_001195800.2:c.505G>A
NM_001195803.2:c.628G>A
NP_000518.1:p.Glu337Lys
NP_000518.1:p.Glu337Lys
NP_001182727.1:p.Glu337Lys
NP_001182728.1:p.Glu296Lys
NP_001182729.1:p.Glu169Lys
NP_001182732.1:p.Glu210Lys
LRG_274t1:c.1009G>A
LRG_274:g.26340G>A
LRG_274p1:p.Glu337Lys
NC_000019.9:g.11221396G>A
NM_000527.4:c.1009G>A

Protein change:

E169K

Links:

dbSNP: rs539080792

NCBI 1000 Genomes Browser:

rs539080792

Molecular consequence:

NM_000527.5:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1009G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.886G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.505G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.628G>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

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
SCV000748113	Iberoamerican FH Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002794046	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 28, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820251	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28964736, 29353225, 29396260, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000748113

Iberoamerican FH Network

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 1, 2016)

germline

research

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

SCV002794046

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 28, 2021)

unknown

clinical testing

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

SCV004820251

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 7, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Description

Variant present in the database from Chile: SCV000748113

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	6	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

Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.

Defesche JC, Stefanutti C, Langslet G, Hopkins PN, Seiz W, Baccara-Dinet MT, Hamon SC, Banerjee P, Kastelein JJP.

J Clin Lipidol. 2017 Nov - Dec;11(6):1338-1346.e7. doi: 10.1016/j.jacl.2017.08.016. Epub 2017 Sep 4. Erratum in: J Clin Lipidol. 2020 Sep - Oct;14(5):742. doi: 10.1016/j.jacl.2020.09.010.

PubMed [citation]

PMID:: 28964736

Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study.

Pek SLT, Dissanayake S, Fong JCW, Lin MX, Chan EZL, Tang JI, Lee CW, Ong HY, Sum CF, Lim SC, Tavintharan S.

Atherosclerosis. 2018 Feb;269:106-116. doi: 10.1016/j.atherosclerosis.2017.12.028. Epub 2017 Dec 27.

PubMed [citation]

PMID:: 29353225

See all PubMed Citations (4)

Details of each submission

From Iberoamerican FH Network, SCV000748113.1

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

Description

%MAF(ExAC):0.01492

#	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, SCV002794046.1

#	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, SCV004820251.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant (also known as p.Glu316Lys in the mature protein) replaces glutamic acid with lysine at codon 337 of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in four individuals affected with familial hypercholesterolemia (PMID: 28964736, 29353225, 29396260; Shakhtshneider et al., 2017). This variant has also been identified in 30/282380 chromosomes (19/30612 South Asian 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		6	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine