NM_000527.5(LDLR):c.91G>A (p.Glu31Lys) AND Familial hypercholesterolemia

Clinical significance:Uncertain significance (Last evaluated: Apr 2, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000775021.3

Allele description [Variation Report for NM_000527.5(LDLR):c.91G>A (p.Glu31Lys)]

NM_000527.5(LDLR):c.91G>A (p.Glu31Lys)

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.91G>A (p.Glu31Lys)
HGVS:
  • NC_000019.10:g.11100246G>A
  • NG_009060.1:g.15866G>A
  • NM_000527.4:c.91G>A
  • NM_000527.5:c.91G>AMANE SELECT
  • NM_001195798.2:c.91G>A
  • NM_001195799.2:c.91G>A
  • NM_001195800.2:c.91G>A
  • NM_001195803.2:c.91G>A
  • NP_000518.1:p.Glu31Lys
  • NP_000518.1:p.Glu31Lys
  • NP_001182727.1:p.Glu31Lys
  • NP_001182728.1:p.Glu31Lys
  • NP_001182729.1:p.Glu31Lys
  • NP_001182732.1:p.Glu31Lys
  • LRG_274t1:c.91G>A
  • LRG_274:g.15866G>A
  • LRG_274p1:p.Glu31Lys
  • NC_000019.9:g.11210922G>A
  • c.91G>A
Protein change:
E31K
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000024; dbSNP: rs776421777
NCBI 1000 Genomes Browser:
rs776421777
Molecular consequence:
  • NM_000527.4:c.91G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.91G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.91G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.91G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.91G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.91G>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
SCV000909118Color Health, Inccriteria provided, single submitter
Uncertain significance
(Apr 2, 2019)
germlineclinical testing

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

SCV001211234Invitaecriteria provided, single submitter
Uncertain significance
(Jan 30, 2019)
germlineclinical testing

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

Description

This variant is a missense variant located in the first LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a Polish individual affected with hypercholesterolemia (PMID: 20145306). This variant has also been identified in 7/282432 chromosomes (7/129154 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

SCV000909118

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

Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.

Chmara M, Wasag B, Zuk M, Kubalska J, Wegrzyn A, Bednarska-Makaruk M, Pronicka E, Wehr H, Defesche JC, Rynkiewicz A, Limon J.

J Appl Genet. 2010;51(1):95-106. doi: 10.1007/BF03195716.

PubMed [citation]
PMID:
20145306
See all PubMed Citations (3)

Details of each submission

From Color Health, Inc, SCV000909118.2

#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, SCV001211234.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces glutamic acid with lysine at codon 31 of the LDLR protein (p.Glu31Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs776421777, ExAC 0.002%). This variant has been observed in an individual with clinical features of familial hypercholesterolemia (PMID: 20145306). ClinVar contains an entry for this variant (Variation ID: 251013). 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: "Benign"; Align-GVGD: "Class C0"). 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: Apr 12, 2021

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