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NM_000527.5(LDLR):c.352G>T (p.Asp118Tyr) AND Homozygous familial hypercholesterolemia

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jul 15, 2020
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:
RCV000454392.5

Allele description [Variation Report for NM_000527.5(LDLR):c.352G>T (p.Asp118Tyr)]

NM_000527.5(LDLR):c.352G>T (p.Asp118Tyr)

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.352G>T (p.Asp118Tyr)
Other names:
FH Naples-3
HGVS:
  • NC_000019.10:g.11105258G>T
  • NG_009060.1:g.20878G>T
  • NM_000527.5:c.352G>TMANE SELECT
  • NM_001195798.2:c.352G>T
  • NM_001195799.2:c.229G>T
  • NM_001195800.2:c.314-2134G>T
  • NM_001195803.2:c.314-1307G>T
  • NP_000518.1:p.Asp118Tyr
  • NP_000518.1:p.Asp118Tyr
  • NP_001182727.1:p.Asp118Tyr
  • NP_001182728.1:p.Asp77Tyr
  • LRG_274t1:c.352G>T
  • LRG_274:g.20878G>T
  • LRG_274p1:p.Asp118Tyr
  • NC_000019.9:g.11215934G>T
  • NM_000527.4:c.352G>T
  • c.352G>T
  • p.(Asp118Tyr)
Protein change:
D118Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001708; dbSNP: rs730882080
NCBI 1000 Genomes Browser:
rs730882080
Molecular consequence:
  • NM_001195800.2:c.314-2134G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1307G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.352G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.352G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.229G>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
unknown functional consequence - Comment(s)
Observations:
3

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
SCV000539518Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Likely pathogenic
(Jul 15, 2020) 		germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown33not providednot providednot providedclinical testing

Citations

PubMed

Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.

Thormaehlen AS, Schuberth C, Won HH, Blattmann P, Joggerst-Thomalla B, Theiss S, Asselta R, Duga S, Merlini PA, Ardissino D, Lander ES, Gabriel S, Rader DJ, Peloso GM, Pepperkok R, Kathiresan S, Runz H.

PLoS Genet. 2015 Feb;11(2):e1004855. doi: 10.1371/journal.pgen.1004855. Erratum in: PLoS Genet. 2015 Mar 17;11(3):e1005060. doi: 10.1371/journal.pgen.1005060.

PubMed [citation]
PMID:
25647241
PMCID:
PMC4409815

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

Do R, Stitziel NO, Won HH, Jørgensen AB, Duga S, Angelica Merlini P, Kiezun A, Farrall M, Goel A, Zuk O, Guella I, Asselta R, Lange LA, Peloso GM, Auer PL; NHLBI Exome Sequencing Project., Girelli D, Martinelli N, Farlow DN, DePristo MA, Roberts R, Stewart AF, et al.

Nature. 2015 Feb 5;518(7537):102-6. doi: 10.1038/nature13917. Epub 2014 Dec 10.

PubMed [citation]
PMID:
25487149
PMCID:
PMC4319990
See all PubMed Citations (14)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000539518.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (14)

Description

The p.Asp118Tyr variant in LDLR has been identified in the heterozygous state in at least 6 individuals with hypercholesterolemia and segregated with disease in > 4 affected relatives with definite or probable familial hypercholesterolemia (FH) from at least 2 families (Bertolini 1999 PMID: 9974426, Bertolini 2000 PMID: 10978268, Liguori 2001 PMID: 11317362, Campagna 2008 PMID: 17196209, Romano 2010 PMID: 20045108, Bertolini 2013 PMID: 23375686, Scicali 2017 PMID: 28958694, Pirillo 2017 PMID: 28965616, Trinder 2019 PMID: 31345425). It has also been reported in 1 homozygote and 3 compound heterozygotes (with additional pathogenic LDLR variants) with hypercholesterolemia, at least 3 of whom had a more severe presentation (Bertolini 2000 PMID: 10978268, Liguori 2001 PMID: 11317362, Campagna 2008 PMID: 17196209, Bertolini 2013 PMID: 23375686). Additionally, this variant has been reported in 2 individuals with early myocardial infarction (Thormaehlen 2015 PMID: 25647241). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183085) and has also been identified in 0.003% (3/111436) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies suggest that the variant has only a mild impact protein function (Bertolini 2013 PMID: 23375686, Thormaehlen 2015 PMID: 25647241). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4_Moderate, PM3, PP1, PM2_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided3not provided3not provided

Last Updated: Sep 29, 2024