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

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Sep 24, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001182458.3

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 (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
SCV001347902Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Sep 24, 2020)
germlineclinical testing

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

SCV001380378Invitaecriteria provided, single submitter
Uncertain significance
(Sep 17, 2019)
germlineclinical testing

PubMed (15)
[See all records that cite these PMIDs]

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

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
See all PubMed Citations (16)

Details of each submission

From Color Health, Inc, SCV001347902.2

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

Description

This missense variant (also known as p.Arg395Gln in the mature protein) replaces arginine with glutamine at codon 416 in the LDLR type B repeat 1 of the LDL binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in seven individuals affected with familial hypercholesterolemia (PMID: 9452095, 11810272, 15241806, 20506408, 22294733, 29353225, 32660911). This variant has been identified in 5/282548 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variant at the same position p.Arg416Trp is a well established Pathogenic variant (Clinvar variation ID 183110). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

From Invitae, SCV001380378.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (15)

Description

This sequence change replaces arginine with glutamine at codon 416 of the LDLR protein (p.Arg416Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs773658037, ExAC 0.01%). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 9452095, 22390909, 10090484, 15241806, 20506408, 11810272, 29353225). This variant is also known as R395Q in the literature. ClinVar contains an entry for this variant (Variation ID: 251752). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg416 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20663204, 23375686, 21376320, 9104431, 25378237, 25921077, 11196104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Last Updated: Aug 27, 2021

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