NM_000527.5(LDLR):c.1247G>A (p.Arg416Gln) AND Familial hypercholesterolemia 1

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jan 21, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000237115.5

Allele description [Variation Report for NM_000527.5(LDLR):c.1247G>A (p.Arg416Gln)]

NM_000527.5(LDLR):c.1247G>A (p.Arg416Gln)

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.1247G>A (p.Arg416Gln)
HGVS:
  • NC_000019.10:g.11113338G>A
  • NG_009060.1:g.28958G>A
  • NM_000527.4:c.1247G>A
  • NM_000527.5:c.1247G>AMANE SELECT
  • NM_001195798.2:c.1247G>A
  • NM_001195799.2:c.1124G>A
  • NM_001195800.2:c.743G>A
  • NM_001195803.2:c.866G>A
  • NP_000518.1:p.Arg416Gln
  • NP_000518.1:p.Arg416Gln
  • NP_001182727.1:p.Arg416Gln
  • NP_001182728.1:p.Arg375Gln
  • NP_001182729.1:p.Arg248Gln
  • NP_001182732.1:p.Arg289Gln
  • LRG_274t1:c.1247G>A
  • LRG_274:g.28958G>A
  • NC_000019.9:g.11224014G>A
  • NM_000527.4(LDLR):c.1247G>A
  • P01130:p.Arg416Gln
  • c.1247G>A
Protein change:
R248Q
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000379; UniProtKB: P01130#VAR_005380; dbSNP: rs773658037
NCBI 1000 Genomes Browser:
rs773658037
Molecular consequence:
  • NM_000527.4:c.1247G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.1247G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1247G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1124G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.743G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.866G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000295324LDLR-LOVD, British Heart Foundationcriteria provided, single submitter
Likely pathogenic
(Mar 25, 2016)
germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000606373Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrumno assertion criteria providedPathogenicgermlineresearch

SCV000607580Fundacion Hipercolesterolemia Familiar - SAFEHEARTcriteria provided, single submitter
Likely pathogenic
(Mar 1, 2016)
germlineresearch

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

SCV001422632Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedUncertain significance
(Jan 22, 2020)
germlinecuration

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

Citation Link,

SCV001432622Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbiacriteria provided, single submitter
Pathogenic
(Jan 21, 2019)
germlineresearch

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes4not providednot provided4not providedliterature only, research
not providedgermlineunknownnot providednot providednot providednot providednot providedresearch, curation

Citations

PubMed

Two novel and two known low-density lipoprotein receptor gene mutations in German patients with familial hypercholesterolemia.

Thiart R, Loubser O, de Villiers JN, Marx MP, Zaire R, Raal FJ, Kotze MJ.

Hum Mutat. 1998;Suppl 1:S232-3. No abstract available.

PubMed [citation]
PMID:
9452095

Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.

Mozas P, Castillo S, Tejedor D, Reyes G, Alonso R, Franco M, Saenz P, Fuentes F, Almagro F, Mata P, PocovĂ­ M.

Hum Mutat. 2004 Aug;24(2):187.

PubMed [citation]
PMID:
15241806
See all PubMed Citations (7)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295324.2

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

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, SCV000606373.1

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

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607580.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)

Description

%MAF(ExAC):0.001658

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

From Broad Institute Rare Disease Group, Broad Institute, SCV001422632.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (5)

Description

The p.Arg416Gln (sometimes called p.Arg395Gln) variant in LDLR has been reported in at least 84 individuals (including 1 German, 1 Spanish, and 1 Dutch individuals) with Familial Hypercholesterolemia (PMID: 20506408, 22294733, 9452095, 15241806, 11810272), and has been identified in 0.005015% (1/19940) of East Asian chromosomes, 0.003982% (1/25114) of European (Finnish) chromosomes, and 0.002327% (3/128928) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs773658037). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic and pathogenic in ClinVar (Variation ID: 251752). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4, PP3 (Richards 2015).

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

From Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia, SCV001432622.1

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

Last Updated: Aug 27, 2021

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