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NM_000527.5(LDLR):c.790A>C (p.Met264Leu) AND Hypercholesterolemia, familial, 1

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 11, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003998536.2

Allele description [Variation Report for NM_000527.5(LDLR):c.790A>C (p.Met264Leu)]

NM_000527.5(LDLR):c.790A>C (p.Met264Leu)

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.790A>C (p.Met264Leu)
HGVS:
  • NC_000019.10:g.11106660A>C
  • NG_009060.1:g.22280A>C
  • NM_000527.5:c.790A>CMANE SELECT
  • NM_001195798.2:c.790A>C
  • NM_001195799.2:c.667A>C
  • NM_001195800.2:c.314-732A>C
  • NM_001195803.2:c.409A>C
  • NP_000518.1:p.Met264Leu
  • NP_000518.1:p.Met264Leu
  • NP_001182727.1:p.Met264Leu
  • NP_001182728.1:p.Met223Leu
  • NP_001182732.1:p.Met137Leu
  • LRG_274t1:c.790A>C
  • LRG_274:g.22280A>C
  • LRG_274p1:p.Met264Leu
  • NC_000019.9:g.11217336A>C
  • NM_000527.4:c.790A>C
Protein change:
M137L
Links:
dbSNP: rs730882088
NCBI 1000 Genomes Browser:
rs730882088
Molecular consequence:
  • NM_001195800.2:c.314-732A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.790A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.790A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.667A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.409A>C - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
no known functional consequence - Comment(s)
Observations:
5

Condition(s)

Name:
Hypercholesterolemia, familial, 1
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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004820213All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Jan 11, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown5not providednot provided108544not providedclinical testing

Citations

PubMed

Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.

Thormaehlen AS, Schuberth C, Won HH, Blattmann P, Joggerst-Thomalla B, Theiss S, Asselta R, Duga S, Merlini PA, Ardissino D, Lander ES, Gabriel S, Rader DJ, Peloso GM, Pepperkok R, Kathiresan S, Runz H.

PLoS Genet. 2015 Feb;11(2):e1004855. doi: 10.1371/journal.pgen.1004855. Erratum in: PLoS Genet. 2015 Mar 17;11(3):e1005060. doi: 10.1371/journal.pgen.1005060.

PubMed [citation]
PMID:
25647241
PMCID:
PMC4409815

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

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004820213.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided5not providednot providedclinical testing PubMed (2)

Description

This missense variant (also known as p.Met243Leu in the mature protein) replaces methionine with leucine at codon 264 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant may not impact LDLR function (PMID: 25647241). This variant has been reported in an individual affected with early-onset myocardial infarction (PMID: 25647241). This variant has been identified in 3/251482 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided5not providednot providednot provided

Last Updated: Sep 1, 2024