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NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu) AND Homozygous familial hypercholesterolemia

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 26, 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:
RCV000826172.6

Allele description [Variation Report for NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)]

NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)

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.2096C>T (p.Pro699Leu)
Other names:
NP_000518.1:p.P699L; NM_000527.5(LDLR):c.2096C>T
HGVS:
  • NC_000019.10:g.11120478C>T
  • NG_009060.1:g.36098C>T
  • NM_000527.5:c.2096C>TMANE SELECT
  • NM_001195798.2:c.2096C>T
  • NM_001195799.2:c.1973C>T
  • NM_001195800.2:c.1592C>T
  • NM_001195803.2:c.1606+245C>T
  • NP_000518.1:p.Pro699Leu
  • NP_000518.1:p.Pro699Leu
  • NP_001182727.1:p.Pro699Leu
  • NP_001182728.1:p.Pro658Leu
  • NP_001182729.1:p.Pro531Leu
  • LRG_274t1:c.2096C>T
  • LRG_274:g.36098C>T
  • LRG_274p1:p.Pro699Leu
  • NC_000019.9:g.11231154C>T
  • NM_000527.4:c.2096C>T
  • P01130:p.Pro699Leu
  • c.2096C>T
Protein change:
P531L
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001600; UniProtKB: P01130#VAR_013955
Molecular consequence:
  • NM_001195803.2:c.1606+245C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.2096C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.2096C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1973C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1592C>T - missense variant - [Sequence Ontology: SO:0001583]
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
SCV000967711Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Likely pathogenic
(Mar 26, 2019) 		germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown33not providednot providednot providedclinical testing

Citations

PubMed

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]
PMID:
11810272

Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia.

Thiart R, Scholtz CL, Vergotine J, Hoogendijk CF, de Villiers JN, Nissen H, Brusgaard K, Gaffney D, Hoffs MS, Vermaak WJ, Kotze MJ.

J Med Genet. 2000 Jul;37(7):514-9.

PubMed [citation]
PMID:
10882754
PMCID:
PMC1734636
See all PubMed Citations (11)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967711.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (11)

Description

The p.Pro699Leu variant in LDLR (also reported as p.Pro678Leu in the literature) has been reported in the heterozygous state at least 11 individuals with familial hypercholesterolemia (FH) and 7 individuals with suspected FH (Thiart 2000, Fouchier 2001, Van Gaal 2001, Huijgen 2011, Tichy 2012, Bertolini 2013, Jannes 2015, Wang 2016, Sharif 2016). It was also identified in 1 individual with homozygous FH who had a second pathogenic loss of function variant in LDLR (Schuster 1995). This variant was also present in this individual's father who had normal cholesterol levels, suggesting reduced penetrance. The p.Pro699Leu variant has been reported by other clinical laboratories in ClinVar (Variation ID# 252219) and has been identified in 9/24032 African chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs201573863). 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 the p.Pro699Leu variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Pro699Leu variant is likely pathogenic. The ACMG/AMP Criteria applied (Richards 2015): PS4, PM2_supporting, PP3.

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

Last Updated: Oct 13, 2024