NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 16, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000775054.15

Allele description [Variation Report for NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys)]

NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys)

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.1069G>A (p.Glu357Lys)

Other names:

FH Paris-7; NM_000527.5(LDLR):c.1069G>A

HGVS:

NC_000019.10:g.11111522G>A
NG_009060.1:g.27142G>A
NM_000527.5:c.1069G>AMANE SELECT
NM_001195798.2:c.1069G>A
NM_001195799.2:c.946G>A
NM_001195800.2:c.565G>A
NM_001195803.2:c.688G>A
NP_000518.1:p.Glu357Lys
NP_000518.1:p.Glu357Lys
NP_001182727.1:p.Glu357Lys
NP_001182728.1:p.Glu316Lys
NP_001182729.1:p.Glu189Lys
NP_001182732.1:p.Glu230Lys
LRG_274t1:c.1069G>A
LRG_274:g.27142G>A
NC_000019.9:g.11222198G>A
NM_000527.4(LDLR):c.1069G>A
NM_000527.4:c.1069G>A
P01130:p.Glu357Lys
c.1069G>A

Protein change:

E189K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001350; UniProtKB: P01130#VAR_005372; dbSNP: rs879254781

NCBI 1000 Genomes Browser:

rs879254781

Molecular consequence:

NM_000527.5:c.1069G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1069G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.946G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.565G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.688G>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
SCV000909154	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 22, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000963893	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1301956, 10735632, 15199436, 28502510, 30179711, 16250003, 28492532
SCV001422598	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2020)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 15199436, 1301956, 28502510, 20506408, 10735632, 25741868 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000909154

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 22, 2019)

germline

clinical testing

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

SCV000963893

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 16, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001422598

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 22, 2020)

germline

curation

PubMed (6)
[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, curation

Citations

PubMed

Corneal arcus as the presenting sign of familial hypercholesterolemia in a young child.

Lock JH, Ross CA, Flaherty M.

J AAPOS. 2018 Dec;22(6):467-468. doi: 10.1016/j.jaapos.2018.03.017. Epub 2018 Sep 1.

PubMed [citation]

PMID:: 30179711

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

See all PubMed Citations (9)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000909154.3

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

Description

This missense variant (also known as p.Glu336Lys in the mature protein and as FH Paris-7) replaces glutamic acid with lysine at codon 357 in the EGF-like repeat B of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional study has shown that this variant may cause defect in protein transport or recycling (PMID: 1301956). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11810272, 1301956, 20506408, 21382890, 23833242). This variant has been reported in compound heterozygosity with c.2034C>A (p.Cys681*) in a young child affected with familial hypercholesterolemia and prominent corneal arcus (PMID: 30179711). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000963893.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

ClinVar contains an entry for this variant (Variation ID: 251649). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 357 of the LDLR protein (p.Glu357Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 10735632, 15199436, 28502510, 30179711; Invitae). This variant is also known as E336K. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. This variant disrupts the p.Glu357 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422598.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

The p.Glu357Lys variant in LDLR has been reported in at least 11 individuals with familial hypercholesterolemia, segregated with disease in 6 affected relatives from 1 family (PMID: 15199436), and was absent from large population studies. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 251649). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1_moderate, PP3, PS4_supporting (Richards 2015).

#	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: Apr 13, 2025

ClinVar

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