NM_000527.5(LDLR):c.337G>A (p.Glu113Lys) AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 17, 2020
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:: RCV001195308.13

Allele description [Variation Report for NM_000527.5(LDLR):c.337G>A (p.Glu113Lys)]

NM_000527.5(LDLR):c.337G>A (p.Glu113Lys)

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.337G>A (p.Glu113Lys)

HGVS:

NC_000019.10:g.11105243G>A
NG_009060.1:g.20863G>A
NM_000527.5:c.337G>AMANE SELECT
NM_001195798.2:c.337G>A
NM_001195799.2:c.214G>A
NM_001195800.2:c.314-2149G>A
NM_001195803.2:c.314-1322G>A
NP_000518.1:p.Glu113Lys
NP_000518.1:p.Glu113Lys
NP_001182727.1:p.Glu113Lys
NP_001182728.1:p.Glu72Lys
LRG_274t1:c.337G>A
LRG_274:g.20863G>A
NC_000019.9:g.11215919G>A
NM_000527.4(LDLR):c.337G>A
NM_000527.4:c.337G>A
NM_000527.5:c.337G>A
c.337G>A
p.Glu113Lys

Protein change:

E113K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001704; dbSNP: rs769383881

NCBI 1000 Genomes Browser:

rs769383881

Molecular consequence:

NM_001195800.2:c.314-2149G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1322G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.337G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.337G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.214G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001365633	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Nov 17, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17539906, 10807540, 16250003, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001365633

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Nov 17, 2020)

germline

clinical testing

PubMed (4)
[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	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia.

Taylor A, Tabrah S, Wang D, Sozen M, Duxbury N, Whittall R, Humphries SE, Norbury G.

Clin Genet. 2007 Jun;71(6):561-8.

PubMed [citation]

PMID:: 17539906

Co-segregation of elevated LDL with a novel mutation (D92K) of the LDL receptor in a kindred with multiple lipoprotein abnormalities.

Wu LL, Hopkins PN, Xin Y, Stephenson SH, Williams RR, Nobe Y, Kajita M, Nakajima T, Emi M.

J Hum Genet. 2000;45(3):154-8.

PubMed [citation]

PMID:: 10807540

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001365633.2

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

Description

The p.Glu113Lys variant in LDLR has been reported in at least 2 individuals with hypercholesterolemia, 1 individual with probable hypercholesterolemia, and segregated with disease in 7 affected relatives from 1 family (Wu 2000 PMID: 10807540, Fouchier 2005 PMID: 16250003, Taylor 2007 PMID: 17539906). It has also been identified in 0.002% (3/128566) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported by other clinical laboratories in ClinVar (Variation ID: 237872). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia (FH). ACMG/AMP Criteria applied: PP1_Strong, PM2_Supporting, PS4_Supporting.

#	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		1	not provided	1	not provided

Last Updated: Oct 13, 2024

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