NM_000527.5(LDLR):c.344G>A (p.Arg115His) AND Familial hypercholesterolemia 1

Clinical significance:Uncertain significance (Last evaluated: Jun 7, 2021)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
7 submissions [Details]
Record status:
current
Accession:
RCV000237176.9

Allele description [Variation Report for NM_000527.5(LDLR):c.344G>A (p.Arg115His)]

NM_000527.5(LDLR):c.344G>A (p.Arg115His)

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.344G>A (p.Arg115His)
Other names:
FH Fukuoka; NM_000527.5(LDLR):c.344G>A
HGVS:
  • NC_000019.10:g.11105250G>A
  • NG_009060.1:g.20870G>A
  • NM_000527.4:c.344G>A
  • NM_000527.5:c.344G>AMANE SELECT
  • NM_001195798.2:c.344G>A
  • NM_001195799.2:c.221G>A
  • NM_001195800.2:c.314-2142G>A
  • NM_001195803.2:c.314-1315G>A
  • NP_000518.1:p.Arg115His
  • NP_000518.1:p.Arg115His
  • NP_001182727.1:p.Arg115His
  • NP_001182728.1:p.Arg74His
  • LRG_274t1:c.344G>A
  • LRG_274:g.20870G>A
  • LRG_274p1:p.Arg115His
  • NC_000019.9:g.11215926G>A
  • c.344G>A
Protein change:
R115H
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000052; dbSNP: rs201102461
NCBI 1000 Genomes Browser:
rs201102461
Molecular consequence:
  • NM_001195800.2:c.314-2142G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1315G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.4:c.344G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.344G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.344G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.221G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
5

Condition(s)

Name:
Familial hypercholesterolemia 1 (FHCL1)
Synonyms:
LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000267384Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Centercriteria provided, single submitter
Uncertain significance
(Mar 18, 2016)
germlinereference population

PubMed (2)
[See all records that cite these PMIDs]

SCV000294641LDLR-LOVD, British Heart Foundationcriteria provided, single submitter
Likely pathogenic
(Mar 25, 2016)
germlineliterature only

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000503144Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foixcriteria provided, single submitter
Likely benign
(Dec 16, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000599327Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorgecriteria provided, single submitter
Pathogenic
(Mar 1, 2016)
germline, not applicablecuration, literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000606093Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrumno assertion criteria providedPathogenicgermlineresearch

SCV000915812Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely pathogenic
(May 1, 2017)
germlineclinical testing

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

Citation Link,

SCV001960908ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, ClinGenreviewed by expert panel
Uncertain significance
(Jun 7, 2021)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes5not providednot provided2604not providedclinical testing, literature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, research, curation
not providednot applicablenot applicablenot providednot providednot providednot providednot providedliterature only
East Asiangermlineunknown1not providednot providednot providednot providedreference population

Citations

PubMed

LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis.

Varret M, Rabés JP, Thiart R, Kotze MJ, Baron H, Cenarro A, Descamps O, Ebhardt M, Hondelijn JC, Kostner GM, Miyake Y, Pocovi M, Schmidt H, Schuster H, Stuhrmann M, Yamamura T, Junien C, Béroud C, Boileau C.

Nucleic Acids Res. 1998 Jan 1;26(1):248-52.

PubMed [citation]
PMID:
9399845
PMCID:
PMC147253

Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia.

Chiou KR, Charng MJ.

Am J Cardiol. 2010 Jun 15;105(12):1752-8. doi: 10.1016/j.amjcard.2010.01.356. Epub 2010 May 4.

PubMed [citation]
PMID:
20538126
See all PubMed Citations (9)

Details of each submission

From Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center, SCV000267384.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1East Asian1not providednot providedreference population PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From LDLR-LOVD, British Heart Foundation, SCV000294641.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (4)
2not provided1not providednot providedliterature only PubMed (4)
3not provided1not providednot providedliterature only PubMed (4)
4not provided1not providednot providedliterature only PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided
3germlineyes1not providednot provided1not providednot providednot provided
4germlineyes1not providednot provided1not providednot providednot provided

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503144.1

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

Description

subject mutated among 2600 FH index cases screened = 1 /previously described in association with FH / Software predictions: Conflicting

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes2600not providednot provided1not providednot providednot provided

From Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599327.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)
2not providednot providednot providednot providedliterature only PubMed (2)

Description

%MAF(ExAC):0.01838

"Assay Description:Heterologous cells (COS-7), FACS assays"
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided
2not applicablenot applicablenot providednot providednot providednot providednot providednot providednot provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, SCV000606093.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000915812.1

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

Description

The LDLR c.344G>A (p.Arg115His) missense variant has been reported in five studies and is found in a total of eight individuals with hypercholesterolemia, including one individual who carried the variant in a compound heterozygous state with a stop-gained variant and seven individuals who carried the variant in a heterozygous state (Khoo et al. 2000; Yu et al. 2002; Kim et al. 2004; Chiou et al. 2011; Mabuchi et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.00234 in the East Asian population of the Genome Aggregation Database. Based on the evidence, the p.Arg115His variant is classified as likely pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, ClinGen, SCV001960908.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000527.5(LDLR):c.344G>A (p.Arg115His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PS3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS3 - Level 1 assays: PMID 12837857: Heterologous cells (COS-7), FACS assays - results - 64% LDLR expression and activity ---- results are below 70% of wild-type, so PS3 is Met.

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

Last Updated: Oct 21, 2021

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