NM_000527.5(LDLR):c.1277T>G (p.Leu426Arg) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 26, 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:: RCV002557526.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1277T>G (p.Leu426Arg)]

NM_000527.5(LDLR):c.1277T>G (p.Leu426Arg)

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.1277T>G (p.Leu426Arg)

HGVS:

NC_000019.10:g.11113368T>G
NG_009060.1:g.28988T>G
NM_000527.5:c.1277T>GMANE SELECT
NM_001195798.2:c.1277T>G
NM_001195799.2:c.1154T>G
NM_001195800.2:c.773T>G
NM_001195803.2:c.896T>G
NP_000518.1:p.Leu426Arg
NP_001182727.1:p.Leu426Arg
NP_001182728.1:p.Leu385Arg
NP_001182729.1:p.Leu258Arg
NP_001182732.1:p.Leu299Arg
LRG_274t1:c.1277T>G
LRG_274:g.28988T>G
NC_000019.9:g.11224044T>G
NM_000527.4:c.1277T>G
p.(Leu426Arg)
p.Leu426Arg

Protein change:

L258R

Links:

dbSNP: rs879254851

NCBI 1000 Genomes Browser:

rs879254851

Molecular consequence:

NM_000527.5:c.1277T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1277T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1154T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.773T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.896T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003443161	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 26, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9763532, 28353356, 33269076, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003443161

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 26, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Citations

PubMed

Mutations in the low-density lipoprotein receptor gene in Chinese familial hypercholesterolemia patients.

Mak YT, Pang CP, Tomlinson B, Zhang J, Chan YS, Mak TW, Masarei JR.

Arterioscler Thromb Vasc Biol. 1998 Oct;18(10):1600-5.

PubMed [citation]

PMID:: 9763532

Causative mutations and premature cardiovascular disease in patients with heterozygous familial hypercholesterolaemia.

Rubba P, Gentile M, Marotta G, Iannuzzi A, Sodano M, De Simone B, Jossa F, Iannuzzo G, Giacobbe C, Di Taranto MD, Fortunato G.

Eur J Prev Cardiol. 2017 Jul;24(10):1051-1059. doi: 10.1177/2047487317702040. Epub 2017 Mar 29.

PubMed [citation]

PMID:: 28353356

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443161.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 426 of the LDLR protein (p.Leu426Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 28353356). ClinVar contains an entry for this variant (Variation ID: 1120245). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Leu426 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9763532, 28353356, 33269076), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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