NM_000527.5(LDLR):c.1294C>G (p.Leu432Val) 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:: RCV000161983.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1294C>G (p.Leu432Val)]

NM_000527.5(LDLR):c.1294C>G (p.Leu432Val)

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.1294C>G (p.Leu432Val)

HGVS:

NC_000019.10:g.11113385C>G
NG_009060.1:g.29005C>G
NM_000527.5:c.1294C>GMANE SELECT
NM_001195798.2:c.1294C>G
NM_001195799.2:c.1171C>G
NM_001195800.2:c.790C>G
NM_001195803.2:c.913C>G
NP_000518.1:p.Leu432Val
NP_000518.1:p.Leu432Val
NP_001182727.1:p.Leu432Val
NP_001182728.1:p.Leu391Val
NP_001182729.1:p.Leu264Val
NP_001182732.1:p.Leu305Val
LRG_274t1:c.1294C>G
LRG_274:g.29005C>G
LRG_274p1:p.Leu432Val
NC_000019.9:g.11224061C>G
NM_000527.4:c.1294C>G
P01130:p.Leu432Val
c.1294C>G

Protein change:

L264V

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000541; UniProtKB: P01130#VAR_007988; dbSNP: rs730882100

NCBI 1000 Genomes Browser:

rs730882100

Molecular consequence:

NM_000527.5:c.1294C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1294C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1171C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.790C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.913C>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Mus musculus chaperonin containing TCP1 subunit 5 (Cct5), transcript variant 1, ...
Mus musculus chaperonin containing TCP1 subunit 5 (Cct5), transcript variant 1, mRNA
gi|1130413406|ref|NM_007637.3|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000189558	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]
SCV000697194	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 (2) [See all records that cite these PMIDs] 15199436, 20045108 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000189558

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]

SCV000697194

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

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

See all PubMed Citations (3)

Details of each submission

From Dept. of Genetics and Pharmacogenomics, Merck Research Labs, SCV000189558.1

#	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, SCV000697194.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: The LDLR c.1294C>G (p.Leu432Val) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/120904 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). This variant has been reported in affected individuals including FH, MI, and CAD, all without strong evidence for causality (i.e. co-segregation data). In addition, LDLR-LOVD, British Heart Foundation classified this variant as likely pathogenic, without evidence to independently evaluate. One published functional study showed that overexpression of p.Leu432Val resulted in intact cellular LDL uptake comparable to wild-type, 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 Y465N (Y444N in legacy name) although the phase not well established. Taken together and due to conflicting lines of evidence, 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 26, 2024

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