NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 7, 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:: RCV002362601.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys)]

NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys)

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.1222G>A (p.Glu408Lys)

Other names:

FH Algeria-1; FH Osaka; NM_000527.5(LDLR):c.1222G>A

HGVS:

NC_000019.10:g.11113313G>A
NG_009060.1:g.28933G>A
NM_000527.5:c.1222G>AMANE SELECT
NM_001195798.2:c.1222G>A
NM_001195799.2:c.1099G>A
NM_001195800.2:c.718G>A
NM_001195803.2:c.841G>A
NP_000518.1:p.Glu408Lys
NP_000518.1:p.Glu408Lys
NP_001182727.1:p.Glu408Lys
NP_001182728.1:p.Glu367Lys
NP_001182729.1:p.Glu240Lys
NP_001182732.1:p.Glu281Lys
LRG_274t1:c.1222G>A
LRG_274:g.28933G>A
LRG_274p1:p.Glu408Lys
NC_000019.9:g.11223989G>A
NM_000527.4:c.1222G>A
P01130:p.Glu408Lys
c.1222G>A

Protein change:

E240K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001379; UniProtKB: P01130#VAR_005378; dbSNP: rs137943601

NCBI 1000 Genomes Browser:

rs137943601

Molecular consequence:

NM_000527.5:c.1222G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1222G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1099G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.718G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.841G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002658943	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 7, 2022)	germline	clinical testing	PubMed (26) [See all records that cite these PMIDs] 12436241, 1301956, 14974088, 15199436, 16250003, 17347910, 17765246, 18503695, 19318025, 19843101, 20236128, 21310417, 21531209, 22698793, 22883975, 25487149, 25637381, 29353225, 29396260, 29502162, 30592178, 32163632, 33418990, 34037665, 9026534, 9698020 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002658943

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 7, 2022)

germline

clinical testing

PubMed (26)
[See all records that cite these PMIDs]

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

Citations

PubMed

Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia.

Amsellem S, Briffaut D, Carrié A, Rabès JP, Girardet JP, Fredenrich A, Moulin P, Krempf M, Reznik Y, Vialettes B, de Gennes JL, Brukert E, Benlian P.

Hum Genet. 2002 Dec;111(6):501-10. Epub 2002 Sep 13.

PubMed [citation]

PMID:: 12436241

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

See all PubMed Citations (26)

Details of each submission

From Ambry Genetics, SCV002658943.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (26)

Description

The p.E408K pathogenic mutation (also known as c.1222G>A), located in coding exon 9 of the LDLR gene, results from a G to A substitution at nucleotide position 1222. The glutamic acid at codon 408 is replaced by lysine, an amino acid with similar properties. This alteration (also referred to as p.E387K) has been reported in multiple unrelated individuals with heterozygous or homozygous familial hypercholesterolemia (FH), has been detected in FH cohorts, and has shown some segregation with disease in families (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Webb JC et al. J. Lipid Res. 1996;37:368-81; Fouchier SW et al. Hum Mutat. 2005 Dec;26(6):550-6; Tichý L et al. Atherosclerosis. 2012;223:401-8; Chan ML et al. Mol Genet Genomic Med. 2019 02;7(2):e00520; Galiano M et al. J Clin Apher. 2020 Jun;35(3):163-171; Meshkov A et al. Genes (Basel). 2021 01;12(1)). Functional studies indicate that this alteration results in deficient protein function (Hobbs HH et al., 1992; Webb JC et al. 1996; Strøm TB et al. Biochem. Biophys. Res. Commun. 2011;408:642-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: Nov 3, 2024

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