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NM_000527.5(LDLR):c.796G>A (p.Asp266Asn) AND Homozygous familial hypercholesterolemia

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Apr 16, 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:
RCV004017503.1

Allele description [Variation Report for NM_000527.5(LDLR):c.796G>A (p.Asp266Asn)]

NM_000527.5(LDLR):c.796G>A (p.Asp266Asn)

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.796G>A (p.Asp266Asn)
Other names:
NM_000527.5(LDLR):c.796G>A
HGVS:
  • NC_000019.10:g.11106666G>A
  • NG_009060.1:g.22286G>A
  • NM_000527.5:c.796G>AMANE SELECT
  • NM_001195798.2:c.796G>A
  • NM_001195799.2:c.673G>A
  • NM_001195800.2:c.314-726G>A
  • NM_001195803.2:c.415G>A
  • NP_000518.1:p.Asp266Asn
  • NP_000518.1:p.Asp266Asn
  • NP_001182727.1:p.Asp266Asn
  • NP_001182728.1:p.Asp225Asn
  • NP_001182732.1:p.Asp139Asn
  • LRG_274t1:c.796G>A
  • LRG_274:g.22286G>A
  • NC_000019.9:g.11217342G>A
  • NM_000527.4(LDLR):c.796G>A
  • NM_000527.4:c.796G>A
  • c.796G>A
Protein change:
D139N
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000469; dbSNP: rs875989907
NCBI 1000 Genomes Browser:
rs875989907
Molecular consequence:
  • NM_001195800.2:c.314-726G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.796G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.796G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.673G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.415G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004847729Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Apr 16, 2019) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Limited mutational heterogeneity in the LDLR gene in familial hypercholesterolemia in Tunisia.

Jelassi A, Jguirim I, Najah M, Abid AM, Boughamoura L, Maatouk F, Rouis M, Boileau C, Rabès JP, Slimane MN, Varret M.

Atherosclerosis. 2009 Apr;203(2):449-53. doi: 10.1016/j.atherosclerosis.2008.07.011. Epub 2008 Jul 23.

PubMed [citation]
PMID:
18757057

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]
PMID:
23375686
See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847729.1

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

Description

The p.Asp266Asn variant in LDLR has been reported in the heterozygous state in 3 individuals with familial hypercholesterolemia (FH), in the homozygous state in 1 individual with a more severe presentation and segregated with disease in 2 affected individuals from 2 families (Fouchier 2001, Slimani 2012, Tichy 2012, Bertolini 2013). It has also been reported by other clinical laboratories in ClinVar (Variation ID 161287) and has identified in 3/251478 pan-ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In addition, another variant involving this codon (p.Asp266Glu) has been identified in individuals with FH and is classified as pathogenic by this laboratory. 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: PM2, PM5, PP3, PS4_Supporting.

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

Last Updated: Sep 29, 2024