NM_000527.5(LDLR):c.1132C>T (p.Gln378Ter) AND Homozygous familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 11, 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:: RCV004017552.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1132C>T (p.Gln378Ter)]

NM_000527.5(LDLR):c.1132C>T (p.Gln378Ter)

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.1132C>T (p.Gln378Ter)

HGVS:

NC_000019.10:g.11111585C>T
NG_009060.1:g.27205C>T
NM_000527.5:c.1132C>TMANE SELECT
NM_001195798.2:c.1132C>T
NM_001195799.2:c.1009C>T
NM_001195800.2:c.628C>T
NM_001195803.2:c.751C>T
NP_000518.1:p.Gln378Ter
NP_001182727.1:p.Gln378Ter
NP_001182728.1:p.Gln337Ter
NP_001182729.1:p.Gln210Ter
NP_001182732.1:p.Gln251Ter
LRG_274:g.27205C>T
NC_000019.9:g.11222261C>T
c.1132C>T

Protein change:

Q210*

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000727; dbSNP: rs879254802

NCBI 1000 Genomes Browser:

rs879254802

Molecular consequence:

NM_000527.5:c.1132C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.1132C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.1009C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195800.2:c.628C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001195803.2:c.751C>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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Homo sapiens dual specificity tyrosine phosphorylation regulated kinase 3 (DYRK3...
Homo sapiens dual specificity tyrosine phosphorylation regulated kinase 3 (DYRK3), transcript variant 1, mRNA
gi|1889562477|ref|NM_003582.4|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004847693	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 11, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19318025, 25846081, 28028493, 11005141, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004847693

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 11, 2019)

germline

clinical testing

PubMed (5)
[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 diagnosis of familial hypercholesterolemia using a DNA-array based platform.

Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, Gomez-Enterria P, Martinez-Faedo C, Forga L, Mata P.

Clin Biochem. 2009 Jun;42(9):899-903. doi: 10.1016/j.clinbiochem.2009.01.017. Epub 2009 Feb 6.

PubMed [citation]

PMID:: 19318025

Novel mutations of low-density lipoprotein receptor gene in China patients with familial hypercholesterolemia.

Fan LL, Lin MJ, Chen YQ, Huang H, Peng DQ, Xia K, Zhao SP, Xiang R.

Appl Biochem Biotechnol. 2015 May;176(1):101-9. doi: 10.1007/s12010-015-1554-x. Epub 2015 Apr 7.

PubMed [citation]

PMID:: 25846081

See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847693.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.Gln378X variant (also described as p.Gln357X in the literature) in LDLR has been reported in 4 individuals familial hypercholesterolemia (FH): in the heterozygous state in 2 individuals (Khoo 2000, Alonso 2009) and in the compound heterozygous state with another pathogenic LDLR variant in 2 individuals (Fan 2015, Du 2016). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 378, 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 pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting, PM3.

#	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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