NM_000527.5(LDLR):c.1898G>T (p.Arg633Leu) AND Familial hypercholesterolemia

Clinical significance:Likely pathogenic (Last evaluated: Feb 3, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001174944.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1898G>T (p.Arg633Leu)]

NM_000527.5(LDLR):c.1898G>T (p.Arg633Leu)

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.1898G>T (p.Arg633Leu)
HGVS:
  • NC_000019.10:g.11120144G>T
  • NG_009060.1:g.35764G>T
  • NM_000527.4:c.1898G>T
  • NM_000527.5:c.1898G>TMANE SELECT
  • NM_001195798.2:c.1898G>T
  • NM_001195799.2:c.1775G>T
  • NM_001195800.2:c.1394G>T
  • NM_001195803.2:c.1517G>T
  • NP_000518.1:p.Arg633Leu
  • NP_000518.1:p.Arg633Leu
  • NP_001182727.1:p.Arg633Leu
  • NP_001182728.1:p.Arg592Leu
  • NP_001182729.1:p.Arg465Leu
  • NP_001182732.1:p.Arg506Leu
  • LRG_274t1:c.1898G>T
  • LRG_274:g.35764G>T
  • LRG_274p1:p.Arg633Leu
  • NC_000019.9:g.11230820G>T
  • c.1898G>T
Protein change:
R465L
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001074; dbSNP: rs754536745
NCBI 1000 Genomes Browser:
rs754536745
Molecular consequence:
  • NM_000527.4:c.1898G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.1898G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1898G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1775G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1394G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1517G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial hypercholesterolemia (FH)
Identifiers:
MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001338397Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Feb 3, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]
PMID:
16250003

Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia.

Huijgen R, Kindt I, Fouchier SW, Defesche JC, Hutten BA, Kastelein JJ, Vissers MN.

Hum Mutat. 2010 Jun;31(6):752-60. doi: 10.1002/humu.21258.

PubMed [citation]
PMID:
20506408
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338397.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: LDLR c.1898G>T (p.Arg633Leu) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251490 control chromosomes (gnomAD). c.1898G>T has been reported in the literature in multiple Dutch individuals affected with Familial Hypercholesterolemia (FH) (e.g. Fouchier_2005, Huijgen_2010, Huijgen_2012, van de rGraaf_2011, Kusters_2013). The JoJoGenetics database reports the variant in 41 patients known in the Netherlands (status June 2019), without providing further information. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missense substitutions affecting the same amino acid residue (i.e. p.Arg633Cys, p.Arg633His) have been reported to be deleterious (internal testing and ClinVar), suggesting that the Arg633 is important for protein function. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Jun 14, 2021

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