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

Clinical significance:Uncertain significance (Last evaluated: Dec 19, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000771221.4

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_000527.5: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
  • NM_000527.4:c.344G>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_000527.5: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]

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
SCV000903315Color Health, Inccriteria provided, single submitter
Uncertain significance
(Dec 19, 2019)
germlineclinical testing

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

SCV001225051Invitaecriteria provided, single submitter
Uncertain significance
(Nov 1, 2019)
germlineclinical testing

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

SCV001456140Natera, Inc.no assertion criteria providedUncertain significance
(Sep 16, 2020)
germlineclinical testing

Description

This missense variant (also known as p.Arg94His in the mature protein) replaces arginine with histidine at codon 115 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant causes a moderately reduced LDLR cell surface expression and increased protein localization to the endoplasmic reticulum (PMID: 12837857). However, clinical relevance of these observations is not clear. This variant has been reported in several individuals of Asian ethnicity affected with hypercholesterolemia (PMID: 11005141, 12417285, 15359125, 20538126). This variant has also been identified in 49/282072 chromosomes (45/19914 East Asian chromosomes; 0.23%) in the general population by the Genome Aggregation Database. Although the relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

SCV000903315

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Identification and characterization of LDL receptor gene mutations in hyperlipidemic Chinese.

Chang JH, Pan JP, Tai DY, Huang AC, Li PH, Ho HL, Hsieh HL, Chou SC, Lin WL, Lo E, Chang CY, Tseng J, Su MT, Lee-Chen GJ.

J Lipid Res. 2003 Oct;44(10):1850-8. Epub 2003 Jul 1.

PubMed [citation]
PMID:
12837857
See all PubMed Citations (12)

Details of each submission

From Color Health, Inc, SCV000903315.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001225051.1

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

Description

This sequence change replaces arginine with histidine at codon 115 of the LDLR protein (p.Arg115His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201102461, ExAC 0.2%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 9399845, 15359125, 29399563, 28502495, 18718593, 28932795, 11005141, 12417285). This variant is also known as R94H in the literature. ClinVar contains an entry for this variant (Variation ID: 225402). This variant has been reported to have conflicting or insufficient data to determine the effect on LDLR protein function (PMID: 12837857, 27821657). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Natera, Inc., SCV001456140.1

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

Last Updated: Dec 4, 2021

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