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NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) AND Homozygous familial hypercholesterolemia

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 23, 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:
RCV000844733.5

Allele description [Variation Report for NM_000527.5(LDLR):c.269A>G (p.Asp90Gly)]

NM_000527.5(LDLR):c.269A>G (p.Asp90Gly)

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.269A>G (p.Asp90Gly)
Other names:
FH London-4; NM_000527.5(LDLR):c.269A>G
HGVS:
  • NC_000019.10:g.11102742A>G
  • NG_009060.1:g.18362A>G
  • NM_000527.5:c.269A>GMANE SELECT
  • NM_001195798.2:c.269A>G
  • NM_001195799.2:c.190+2397A>G
  • NM_001195800.2:c.269A>G
  • NM_001195803.2:c.269A>G
  • NP_000518.1:p.Asp90Gly
  • NP_000518.1:p.Asp90Gly
  • NP_001182727.1:p.Asp90Gly
  • NP_001182729.1:p.Asp90Gly
  • NP_001182732.1:p.Asp90Gly
  • LRG_274t1:c.269A>G
  • LRG_274:g.18362A>G
  • LRG_274p1:p.Asp90Gly
  • NC_000019.9:g.11213418A>G
  • NM_000527.4:c.269A>G
  • P01130:p.Asp90Gly
  • c.269A>G
Protein change:
D90G
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001676; UniProtKB: P01130#VAR_005310; dbSNP: rs771019366
NCBI 1000 Genomes Browser:
rs771019366
Molecular consequence:
  • NM_001195799.2:c.190+2397A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.269A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.269A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.269A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.269A>G - missense variant - [Sequence Ontology: SO:0001583]
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
SCV000732011Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Likely pathogenic
(Oct 23, 2017) 		germlineclinical testing

PubMed (6)
[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

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]
PMID:
1301956

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 (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000732011.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)

Description

The p.Asp90Gly variant in LDLR has been reported in 5 individuals with familial hypercholesterolemia (FH: 4 in the heterozygous state, 1 in the homozygous state ; Hobbs 1992, Amsellem 2002, Bunn 2002, Do 2015). This variant has also been rep orted in ClinVar (Variation ID# 226313) with one submission (SCV000503124.1) quo ting co-segregation with disease. In vitro functional studies provide some evide nce that the p.Asp90Gly variant may impact protein function (Hobbs 1992). This v ariant has also been identified in 1/66740 European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs771019366). T his frequency is low enough to be consistent with the frequency of FH in the gen eral population. Computational prediction tools and conservation analysis sugges t that the p.Asp90Gly variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Other missense variants at t his position have been reported in individuals with hypercholesterolemia (HGMD d atabase, Stenson 2017). In summary, although additional studies are required to fully establish its clinical significance, the p.Asp90Gly variant is likely pat hogenic. ACMG/AMP Criteria applied: PM2; PM5_supporting; PP3; PS3_Supporting; PS 4_Supporting (Richards 2015).

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

Last Updated: Sep 29, 2024