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NM_000527.5(LDLR):c.907C>T (p.Arg303Trp) AND Cardiovascular phenotype

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Apr 4, 2022
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:
RCV002444607.9

Allele description [Variation Report for NM_000527.5(LDLR):c.907C>T (p.Arg303Trp)]

NM_000527.5(LDLR):c.907C>T (p.Arg303Trp)

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.907C>T (p.Arg303Trp)
Other names:
NM_000527.5(LDLR):c.907C>T
HGVS:
  • NC_000019.10:g.11107481C>T
  • NG_009060.1:g.23101C>T
  • NM_000527.5:c.907C>TMANE SELECT
  • NM_001195798.2:c.907C>T
  • NM_001195799.2:c.784C>T
  • NM_001195800.2:c.403C>T
  • NM_001195803.2:c.526C>T
  • NP_000518.1:p.Arg303Trp
  • NP_000518.1:p.Arg303Trp
  • NP_001182727.1:p.Arg303Trp
  • NP_001182728.1:p.Arg262Trp
  • NP_001182729.1:p.Arg135Trp
  • NP_001182732.1:p.Arg176Trp
  • LRG_274t1:c.907C>T
  • LRG_274:g.23101C>T
  • LRG_274p1:p.Arg303Trp
  • NC_000019.9:g.11218157C>T
  • NM_000527.4:c.907C>T
  • c.907C>T
  • p.Arg303Trp
Protein change:
R135W
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000512; dbSNP: rs151207122
NCBI 1000 Genomes Browser:
rs151207122
Molecular consequence:
  • NM_000527.5:c.907C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.907C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.784C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.403C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.526C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002683064Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Apr 4, 2022) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.

Lange LA, Hu Y, Zhang H, Xue C, Schmidt EM, Tang ZZ, Bizon C, Lange EM, Smith JD, Turner EH, Jun G, Kang HM, Peloso G, Auer P, Li KP, Flannick J, Zhang J, Fuchsberger C, Gaulton K, Lindgren C, Locke A, Manning A, et al.

Am J Hum Genet. 2014 Feb 6;94(2):233-45. doi: 10.1016/j.ajhg.2014.01.010.

PubMed [citation]
PMID:
24507775
PMCID:
PMC3928660

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

Do R, Stitziel NO, Won HH, Jørgensen AB, Duga S, Angelica Merlini P, Kiezun A, Farrall M, Goel A, Zuk O, Guella I, Asselta R, Lange LA, Peloso GM, Auer PL; NHLBI Exome Sequencing Project., Girelli D, Martinelli N, Farlow DN, DePristo MA, Roberts R, Stewart AF, et al.

Nature. 2015 Feb 5;518(7537):102-6. doi: 10.1038/nature13917. Epub 2014 Dec 10.

PubMed [citation]
PMID:
25487149
PMCID:
PMC4319990
See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV002683064.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

The p.R303W variant (also known as c.907C>T), located in coding exon 6 of the LDLR gene, results from a C to T substitution at nucleotide position 907. The arginine at codon 303 is replaced by tryptophan, an amino acid with dissimilar properties. This variant (also referred to as R282W) has been detected in cohorts with hypercholesterolemia; however, in several cases, clinical details were limited, and, in one case, it co-occurred with another variant in LDLR (Arca M. Atherosclerosis. 1998 Jan;136(1):187-94; Pirillo A et al. Atheroscler Suppl, 2017 Oct;29:17-24; Lange LA et al. Am. J. Hum. Genet., 2014 Feb;94:233-45; Sun YV et al. Circ Genom Precis Med, 2018 12;11). This variant has also been detected in an early onset myocardial infarction (MI) cohort and MI-free controls, as well as in a low LDL-C and healthy exome cohorts (Do R et al. Nature, 2015 Feb;518:102-6; Lange LA et al. Am. J. Hum. Genet., 2014 Feb;94:233-45; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). This alteration impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 7 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

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

Last Updated: Oct 26, 2024