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NM_000527.5(LDLR):c.1393T>A (p.Tyr465Asn) AND not provided

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Sep 6, 2016
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:
RCV000161986.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1393T>A (p.Tyr465Asn)]

NM_000527.5(LDLR):c.1393T>A (p.Tyr465Asn)

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.1393T>A (p.Tyr465Asn)
Other names:
NM_000527.5(LDLR):c.1393T>A; p.Tyr465Asn
HGVS:
  • NC_000019.10:g.11113569T>A
  • NG_009060.1:g.29189T>A
  • NM_000527.5:c.1393T>AMANE SELECT
  • NM_001195798.2:c.1393T>A
  • NM_001195799.2:c.1270T>A
  • NM_001195800.2:c.889T>A
  • NM_001195803.2:c.1012T>A
  • NP_000518.1:p.Tyr465Asn
  • NP_000518.1:p.Tyr465Asn
  • NP_001182727.1:p.Tyr465Asn
  • NP_001182728.1:p.Tyr424Asn
  • NP_001182729.1:p.Tyr297Asn
  • NP_001182732.1:p.Tyr338Asn
  • LRG_274t1:c.1393T>A
  • LRG_274:g.29189T>A
  • LRG_274p1:p.Tyr465Asn
  • NC_000019.9:g.11224245T>A
  • NM_000527.4:c.1393T>A
  • c.1393T>A
Protein change:
Y297N
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001420; dbSNP: rs730882101
NCBI 1000 Genomes Browser:
rs730882101
Molecular consequence:
  • NM_000527.5:c.1393T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1393T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1270T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.889T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1012T>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
no known functional consequence - Comment(s)

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000189561Dept. of Genetics and Pharmacogenomics, Merck Research Labs
no classification provided

(in vitro)
not providednot applicablein vitro

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

SCV000697196Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Uncertain significance
(Sep 6, 2016)
germlineclinical testing

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

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providednot applicablenot applicablenot providednot providednot providednot providednot providedin vitro

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

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]
PMID:
15199436

Details of each submission

From Dept. of Genetics and Pharmacogenomics, Merck Research Labs, SCV000189561.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedin vitro PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not applicablenot applicablenot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697196.1

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

Description

Variant summary: The LDLR c.1393T>A (p.Tyr465Asn) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/134150 control chromosomes at a frequency of 0.0000149, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). It was reported in FH and early MI patients, however without strong evidence for pathogenicity such as co-segregation. A functional study demonstrated the variant not to have an impact on LDL uptake indicating a neutral outcome, although authors did list variant as a hypomorphic variant and speculated that the compound heterozygosity of two hypomorphic variants (Y465N and L432V for example) could impair receptor activities in the range of a classic FH-mutant (Thormaehlen_2015). JoJo Genetics noted that variant of interest often co-occured with L432V (L411V in legacy name) although the phase not well established. Taken together, this variant is classified as VUS until more evidence becomes available.

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

Last Updated: Oct 13, 2024