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NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg) AND Hypercholesterolemia, familial, 1

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Aug 14, 2019
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:
RCV001537878.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg)]

NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg)

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.1327T>C (p.Trp443Arg)
HGVS:
  • NC_000019.10:g.11113418T>C
  • NG_009060.1:g.29038T>C
  • NM_000527.5:c.1327T>CMANE SELECT
  • NM_001195798.2:c.1327T>C
  • NM_001195799.2:c.1204T>C
  • NM_001195800.2:c.823T>C
  • NM_001195803.2:c.946T>C
  • NP_000518.1:p.Trp443Arg
  • NP_001182727.1:p.Trp443Arg
  • NP_001182728.1:p.Trp402Arg
  • NP_001182729.1:p.Trp275Arg
  • NP_001182732.1:p.Trp316Arg
  • LRG_274t1:c.1327T>C
  • LRG_274:g.29038T>C
  • NC_000019.9:g.11224094T>C
  • NM_000527.4:c.1327T>C
Protein change:
W275R
Links:
dbSNP: rs773566855
NCBI 1000 Genomes Browser:
rs773566855
Molecular consequence:
  • NM_000527.5:c.1327T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1327T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1204T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.823T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.946T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001754787Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Aug 14, 2019) 		germlineclinical testing

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

Help

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

Details of each submission

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001754787.1

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

Description

This c.1327T>C (p.Trp443Arg) variant in the LDLR gene has been reported in two Russian families affected with familial hypercholesterolemia (PMID 15477777, 28290784). This variant is extremely rare in the general population (1/251246 alleles in gnomAD) and is located within the LDL-receptor class B repeat 2 region critical for ligand release and recycling of the receptor [PMID: 3494949]. Other missense variants at this same amino acid position have been reported as causative for FH supporting the functional importance of this locus. In-silico predictions suggest a damaging effect of this variant. The c.1327T>C (p.Trp443Arg) variant in the LDLR gene is thus classified as likely pathogenic.

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

Last Updated: Nov 3, 2024