NM_000527.5(LDLR):c.564C>G (p.Tyr188Ter) AND Homozygous familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 6, 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:: RCV004017227.1

Allele description [Variation Report for NM_000527.5(LDLR):c.564C>G (p.Tyr188Ter)]

NM_000527.5(LDLR):c.564C>G (p.Tyr188Ter)

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.564C>G (p.Tyr188Ter)

Other names:

Y167*; FH Druze; NP_000518.1:p.Y188*

HGVS:

NC_000019.10:g.11105470C>G
NG_009060.1:g.21090C>G
NM_000527.5:c.564C>GMANE SELECT
NM_001195798.2:c.564C>G
NM_001195799.2:c.441C>G
NM_001195800.2:c.314-1922C>G
NM_001195803.2:c.314-1095C>G
NP_000518.1:p.Tyr188Ter
NP_000518.1:p.Tyr188Ter
NP_001182727.1:p.Tyr188Ter
NP_001182728.1:p.Tyr147Ter
LRG_274t1:c.564C>G
LRG_274:g.21090C>G
LRG_274p1:p.Tyr188Ter
NC_000019.9:g.11216146C>G
NM_000527.4:c.564C>G
c.564C>G
p.Tyr188*

Protein change:

Y147*; TYR167TER

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001763; OMIM: 606945.0045; dbSNP: rs121908034

NCBI 1000 Genomes Browser:

rs121908034

Molecular consequence:

NM_001195800.2:c.314-1922C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1095C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.564C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.564C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.441C>G - 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
SCV004847646	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 6, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17142622, 8882879, 1734722, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004847646

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 6, 2019)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk.

Humphries SE, Whittall RA, Hubbart CS, Maplebeck S, Cooper JA, Soutar AK, Naoumova R, Thompson GR, Seed M, Durrington PN, Miller JP, Betteridge DJ, Neil HA; Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee..

J Med Genet. 2006 Dec;43(12):943-9. Erratum in: J Med Genet. 2009 Dec;46(12):861. J Med Genet. 2010 Dec;47(12):862.

PubMed [citation]

PMID:: 17142622
PMCID:: PMC2563208

Molecular genetics of familial hypercholesterolemia in Israel.

Reshef A, Nissen H, Triger L, Hensen TS, Eliav O, Schurr D, Safadi R, Gare M, Leitersdorf E.

Hum Genet. 1996 Nov;98(5):581-6.

PubMed [citation]

PMID:: 8882879

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847646.1

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

Description

The p.Tyr188X variant in LDLR has been reported in 1 homozygous individual with severe hypercholesterolemia, 2 heterozygous individuals with hypercholesterolemia, and segregated with disease in 5 affected individuals from 1 family (Landsberger 1992. Humphries 2006). It was absent from large population studies, but is reported in ClinVar (Variation ID: 3727). This nonsense variant leads to a premature termination codon at position 188, 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 hypercholesterolemia. In vitro functional studies support an impact on protein function (Landsberger 1996). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2, PM3, PP1_Moderate, PS3_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		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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