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NM_000527.5(LDLR):c.662A>G (p.Asp221Gly) AND Homozygous familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 3, 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:
RCV000844743.6

Allele description [Variation Report for NM_000527.5(LDLR):c.662A>G (p.Asp221Gly)]

NM_000527.5(LDLR):c.662A>G (p.Asp221Gly)

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.662A>G (p.Asp221Gly)
Other names:
NP_000518.1:p.D221G; NM_000527.5(LDLR):c.662A>G
HGVS:
  • NC_000019.10:g.11105568A>G
  • NG_009060.1:g.21188A>G
  • NM_000527.5:c.662A>GMANE SELECT
  • NM_001195798.1:c.662A>G
  • NM_001195798.2:c.662A>G
  • NM_001195799.2:c.539A>G
  • NM_001195800.2:c.314-1824A>G
  • NM_001195803.2:c.314-997A>G
  • NP_000518.1:p.Asp221Gly
  • NP_000518.1:p.Asp221Gly
  • NP_001182727.1:p.Asp221Gly
  • NP_001182728.1:p.Asp180Gly
  • LRG_274t1:c.662A>G
  • LRG_274:g.21188A>G
  • LRG_274p1:p.Asp221Gly
  • NC_000019.9:g.11216244A>G
  • NM_000527.4:c.662A>G
  • NM_000527.5:c.662A>G
  • P01130:p.Asp221Gly
  • c.662A>G
  • p.(Asp221Gly)
Protein change:
D180G
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000096; UniProtKB: P01130#VAR_005332
Molecular consequence:
  • NM_001195800.2:c.314-1824A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-997A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.662A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.662A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.539A>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
functional variant [Sequence Ontology: SO:0001536] - Comment(s)
Observations:
2

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
SCV000711396Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Pathogenic
(Mar 3, 2019) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown22not providednot providednot providedclinical testing

Citations

PubMed

Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.

Chmara M, Wasag B, Zuk M, Kubalska J, Wegrzyn A, Bednarska-Makaruk M, Pronicka E, Wehr H, Defesche JC, Rynkiewicz A, Limon J.

J Appl Genet. 2010;51(1):95-106. doi: 10.1007/BF03195716.

PubMed [citation]
PMID:
20145306

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
See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711396.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (6)

Description

The p.Asp221Gly variant in LDLR has been reported in >75 individuals with familial hypercholesterolemia (FH), including in 4 homozygotes who presented with more severe disease (Hobbs 1992, Chmara 2010, Bertolini 2013). However, not all individuals carrying this variant presented with high cholesterol levels (Bertolini 2013, Thormaehlen 2015). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 183092) and has been identified in 13/111132 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs373822756). Please note that this frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies provide some evidence that the p.Asp221Gly variant may impact protein function (Thormaehlen 2015). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in affected individuals, low frequency in the general population, computational and functional evidence. The ACMG/AMP Criteria applied: PS4, PM3_Strong, PP3, PS3_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not provided2not provided

Last Updated: Oct 13, 2024