NM_000527.5(LDLR):c.204C>A (p.Cys68Ter) AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 2, 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:: RCV004017536.1

Allele description [Variation Report for NM_000527.5(LDLR):c.204C>A (p.Cys68Ter)]

NM_000527.5(LDLR):c.204C>A (p.Cys68Ter)

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.204C>A (p.Cys68Ter)

HGVS:

NC_000019.10:g.11102677C>A
NG_009060.1:g.18297C>A
NM_000527.5:c.204C>AMANE SELECT
NM_001195798.2:c.204C>A
NM_001195799.2:c.190+2332C>A
NM_001195800.2:c.204C>A
NM_001195803.2:c.204C>A
NP_000518.1:p.Cys68Ter
NP_000518.1:p.Cys68Ter
NP_001182727.1:p.Cys68Ter
NP_001182729.1:p.Cys68Ter
NP_001182732.1:p.Cys68Ter
LRG_274t1:c.204C>A
LRG_274:g.18297C>A
LRG_274p1:p.Cys68Ter
NC_000019.9:g.11213353C>A
NM_000527.4:c.204C>A
c.204C>A

Protein change:

C68*

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000681; dbSNP: rs879254437

NCBI 1000 Genomes Browser:

rs879254437

Molecular consequence:

NM_001195799.2:c.190+2332C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.204C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.204C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195800.2:c.204C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195803.2:c.204C>A - 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
SCV004847681	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Apr 2, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17094996, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004847681

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Apr 2, 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

Genetic defects causing familial hypercholesterolaemia: identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic.

Tosi I, Toledo-Leiva P, Neuwirth C, Naoumova RP, Soutar AK.

Atherosclerosis. 2007 Sep;194(1):102-11. Epub 2006 Nov 13.

PubMed [citation]

PMID:: 17094996

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, SCV004847681.1

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

Description

The p.Cys68X variant in LDLR (also reported as p.Cys47X in the literature) has been reported in the heterozygous state in 1 individual with familial hypercholesterolemia (FH; Tosi 2007) and has also been reported in ClinVar (Variation ID: 251077). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 68, 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, 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: Sep 29, 2024

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