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NM_000527.5(LDLR):c.373C>T (p.Gln125Ter) AND Homozygous familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 17, 2017
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:
RCV000844734.4

Allele description [Variation Report for NM_000527.5(LDLR):c.373C>T (p.Gln125Ter)]

NM_000527.5(LDLR):c.373C>T (p.Gln125Ter)

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.373C>T (p.Gln125Ter)
Other names:
FH Foggia-2
HGVS:
  • NC_000019.10:g.11105279C>T
  • NG_009060.1:g.20899C>T
  • NM_000527.5:c.373C>TMANE SELECT
  • NM_001195798.2:c.373C>T
  • NM_001195799.2:c.250C>T
  • NM_001195800.2:c.314-2113C>T
  • NM_001195803.2:c.314-1286C>T
  • NP_000518.1:p.Gln125Ter
  • NP_000518.1:p.Gln125Ter
  • NP_001182727.1:p.Gln125Ter
  • NP_001182728.1:p.Gln84Ter
  • LRG_274t1:c.373C>T
  • LRG_274:g.20899C>T
  • LRG_274p1:p.Gln125Ter
  • NC_000019.9:g.11215955C>T
  • NM_000527.4:c.373C>T
  • c.373C>T
  • p.Gln125X
Protein change:
Q125*
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000404; dbSNP: rs875989899
NCBI 1000 Genomes Browser:
rs875989899
Molecular consequence:
  • NM_001195800.2:c.314-2113C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1286C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.373C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001195798.2:c.373C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001195799.2:c.250C>T - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000731746Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Pathogenic
(Oct 17, 2017) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, Pes G, Postiglione A, Stefanutti C, Blotta I, Pisciotta L, Rolleri M, Langheim S, Ghisellini M, Rabbone I, Calandra S.

Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E41-52.

PubMed [citation]
PMID:
10978268

Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia.

Bertolini S, Cassanelli S, Garuti R, Ghisellini M, Simone ML, Rolleri M, Masturzo P, Calandra S.

Arterioscler Thromb Vasc Biol. 1999 Feb;19(2):408-18.

PubMed [citation]
PMID:
9974426
See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731746.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)

Description

The p.Gln125X variant in LDLR has been reported in 3 individuals with clinical f eatures of familial hypercholesterolemia (FH), including one homozygous individu al with severe FH, segregated with disease in 3 affected relatives from 2 famili es (Bertolini 1999, Bertolini 2000, Bertolini 2013), and was absent from large p opulation studies. In vitro functional studies measuring LDL receptor activity i n cultured skin fibroblasts from the homozygous individual with severe FH show s everely impaired protein function, with less than 5% receptor residual activity (Bertolini 2013). This nonsense variant leads to a premature termination codon a t position 125, which is predicted to lead to a truncated or absent protein. Het erozygous loss of function of the LDLR gene is an established disease mechanism in FH. In summary, this variant meets criteria to be classified as pathogenic fo r familial hypercholesterolemia in an autosomal dominant manner based upon segre gation studies, absence from controls, predicted impact to the protein and funct ional evidence.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

Last Updated: May 1, 2024