NM_000527.5(LDLR):c.1843G>A (p.Glu615Lys) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 6, 2023
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:: RCV000819650.7

Allele description [Variation Report for NM_000527.5(LDLR):c.1843G>A (p.Glu615Lys)]

NM_000527.5(LDLR):c.1843G>A (p.Glu615Lys)

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.1843G>A (p.Glu615Lys)

HGVS:

NC_000019.10:g.11116996G>A
NG_009060.1:g.32616G>A
NM_000527.5:c.1843G>AMANE SELECT
NM_001195798.2:c.1843G>A
NM_001195799.2:c.1720G>A
NM_001195800.2:c.1339G>A
NM_001195803.2:c.1462G>A
NP_000518.1:p.Glu615Lys
NP_000518.1:p.Glu615Lys
NP_001182727.1:p.Glu615Lys
NP_001182728.1:p.Glu574Lys
NP_001182729.1:p.Glu447Lys
NP_001182732.1:p.Glu488Lys
LRG_274t1:c.1843G>A
LRG_274:g.32616G>A
LRG_274p1:p.Glu615Lys
NC_000019.9:g.11227672G>A
NM_000527.4:c.1843G>A
c.1843G>A

Protein change:

E447K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000805; dbSNP: rs879255045

NCBI 1000 Genomes Browser:

rs879255045

Molecular consequence:

NM_000527.5:c.1843G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1843G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1720G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1339G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1462G>A - 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
SCV000960321	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 6, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 35222550, 11810272, 20506408, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000960321

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 6, 2023)

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

Fast and Easy Nanopore Sequencing Workflow for Rapid Genetic Testing of Familial Hypercholesterolemia.

Soufi M, Bedenbender S, Ruppert V, Kurt B, Schieffer B, Schaefer JR.

Front Genet. 2022;13:836231. doi: 10.3389/fgene.2022.836231.

PubMed [citation]

PMID:: 35222550
PMCID:: PMC8864071

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]

PMID:: 11810272

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000960321.4

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

Description

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. This variant disrupts the p.Glu615 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 35222550), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 252063). This variant is also known as E594K. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 11810272, 20506408; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 615 of the LDLR protein (p.Glu615Lys).

#	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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