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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000189561	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	no classification provided (in vitro)	not provided	not applicable	in vitro	PubMed (1) [See all records that cite this PMID]
SCV000697196	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Sep 6, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000189561

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

no classification provided

(in vitro)

not provided

not applicable

in vitro

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

SCV000697196

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Sep 6, 2016)

germline

clinical testing

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

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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