NM_000527.5(LDLR):c.922G>T (p.Glu308Ter) AND Homozygous familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 8, 2018
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:: RCV004017734.1

Allele description [Variation Report for NM_000527.5(LDLR):c.922G>T (p.Glu308Ter)]

NM_000527.5(LDLR):c.922G>T (p.Glu308Ter)

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.922G>T (p.Glu308Ter)

HGVS:

NC_000019.10:g.11107496G>T
NG_009060.1:g.23116G>T
NM_000527.5:c.922G>TMANE SELECT
NM_001195798.2:c.922G>T
NM_001195799.2:c.799G>T
NM_001195800.2:c.418G>T
NM_001195803.2:c.541G>T
NP_000518.1:p.Glu308Ter
NP_000518.1:p.Glu308Ter
NP_001182727.1:p.Glu308Ter
NP_001182728.1:p.Glu267Ter
NP_001182729.1:p.Glu140Ter
NP_001182732.1:p.Glu181Ter
LRG_274t1:c.922G>T
LRG_274:g.23116G>T
LRG_274p1:p.Glu308Ter
NC_000019.9:g.11218172G>T
NM_000527.4:c.922G>T

Protein change:

E140*

Links:

dbSNP: rs879254721

NCBI 1000 Genomes Browser:

rs879254721

Molecular consequence:

NM_000527.5:c.922G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.922G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.799G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195800.2:c.418G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195803.2:c.541G>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV004848164	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 8, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004848164

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 8, 2018)

germline

clinical testing

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

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

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, SCV004848164.1

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

Description

The p.Glu308X variant in LDLR has not been reported in individual with familial hypercholesterolemia or large population studies. This nonsense variant leads to a premature termination codon at position 308, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in individuals with familial hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon the predicted impact to the protein and absence from controls. 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: Sep 1, 2024

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