NM_000527.5(LDLR):c.520G>T (p.Glu174Ter) AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 16, 2019
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:: RCV004017597.1

Allele description [Variation Report for NM_000527.5(LDLR):c.520G>T (p.Glu174Ter)]

NM_000527.5(LDLR):c.520G>T (p.Glu174Ter)

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.520G>T (p.Glu174Ter)

HGVS:

NC_000019.10:g.11105426G>T
NG_009060.1:g.21046G>T
NM_000527.5:c.520G>TMANE SELECT
NM_001195798.2:c.520G>T
NM_001195799.2:c.397G>T
NM_001195800.2:c.314-1966G>T
NM_001195803.2:c.314-1139G>T
NP_000518.1:p.E174*
NP_000518.1:p.Glu174Ter
NP_000518.1:p.Glu174Ter
NP_001182727.1:p.Glu174Ter
NP_001182728.1:p.Glu133Ter
LRG_274t1:c.520G>T
LRG_274t1:c.520G>T
LRG_274:g.21046G>T
LRG_274p1:p.E174*
LRG_274p1:p.Glu174Ter
NC_000019.9:g.11216102G>T
NM_000527.4:c.520G>T

Protein change:

E133*

Links:

dbSNP: rs777326720

NCBI 1000 Genomes Browser:

rs777326720

Molecular consequence:

NM_001195800.2:c.314-1966G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1139G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.520G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.520G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.397G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

SLC35C2 [Gracilinanus agilis]
SLC35C2 [Gracilinanus agilis]
Gene ID:123235268

Gene
CORT_0A10940 [Candida orthopsilosis Co 90-125]
CORT_0A10940 [Candida orthopsilosis Co 90-125]
Gene ID:14537417

Gene
Pdw03_5644 [Penicillium digitatum]
Pdw03_5644 [Penicillium digitatum]
Gene ID:26229060

Gene

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
SCV004847687	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Apr 16, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27050191, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004847687

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Apr 16, 2019)

germline

clinical testing

PubMed (2)
[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

Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.

Khera AV, Won HH, Peloso GM, Lawson KS, Bartz TM, Deng X, van Leeuwen EM, Natarajan P, Emdin CA, Bick AG, Morrison AC, Brody JA, Gupta N, Nomura A, Kessler T, Duga S, Bis JC, van Duijn CM, Cupples LA, Psaty B, Rader DJ, Danesh J, et al.

J Am Coll Cardiol. 2016 Jun 7;67(22):2578-89. doi: 10.1016/j.jacc.2016.03.520. Epub 2016 Apr 3.

PubMed [citation]

PMID:: 27050191
PMCID:: PMC5405769

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847687.1

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

Description

The p.Glu174X variant in LDLR has been reported in the heterozygous state in 1 individual with coronary artery disease (Khera 2016) and 1 individual with familial hypercholesterolemia (FH; ClinVar submission accession: SCV000484758.1). It has also been identified in 0.007% (2/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 174, which is predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. 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 FH. ACMG/AMP Criteria applied: PVS1, PM2.

#	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: May 7, 2024

ClinVar

Relating variation to medicine