NM_000527.5(LDLR):c.1510A>G (p.Lys504Glu) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 3, 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:: RCV001175675.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1510A>G (p.Lys504Glu)]

NM_000527.5(LDLR):c.1510A>G (p.Lys504Glu)

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.1510A>G (p.Lys504Glu)

HGVS:

NC_000019.10:g.11113686A>G
NG_009060.1:g.29306A>G
NM_000527.5:c.1510A>GMANE SELECT
NM_001195798.2:c.1510A>G
NM_001195799.2:c.1387A>G
NM_001195800.2:c.1006A>G
NM_001195803.2:c.1129A>G
NP_000518.1:p.Lys504Glu
NP_000518.1:p.Lys504Glu
NP_001182727.1:p.Lys504Glu
NP_001182728.1:p.Lys463Glu
NP_001182729.1:p.Lys336Glu
NP_001182732.1:p.Lys377Glu
LRG_274t1:c.1510A>G
LRG_274:g.29306A>G
NC_000019.9:g.11224362A>G
NM_000527.4(LDLR):c.1510A>G
NM_000527.4:c.1510A>G
c.1510A>G

Protein change:

K336E

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001446; dbSNP: rs730882103

NCBI 1000 Genomes Browser:

rs730882103

Molecular consequence:

NM_000527.5:c.1510A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1510A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1387A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1006A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1129A>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

Condition(s)

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

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Mus musculus zinc finger, CCHC domain containing 17 (Zcchc17), mRNA
Mus musculus zinc finger, CCHC domain containing 17 (Zcchc17), mRNA
gi|260281876|ref|NM_153160.4|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001339364	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 3, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15199436, 25487149, 25647241, 27784735, 25741868
SCV001422594	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 22, 2020)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 15199436, 25647241, 25741868 Citation Link,
SCV003265100	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 30, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15199436, 19318025, 25487149, 25647241, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001339364

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 3, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001422594

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 22, 2020)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV003265100

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 30, 2021)

germline

clinical testing

PubMed (5)
[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, curation

Citations

PubMed

Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship.

Sánchez-Hernández RM, Civeira F, Stef M, Perez-Calahorra S, Almagro F, Plana N, Novoa FJ, Sáenz-Aranzubía P, Mosquera D, Soler C, Fuentes FJ, Brito-Casillas Y, Real JT, Blanco-Vaca F, Ascaso JF, Pocovi M.

Circ Cardiovasc Genet. 2016 Dec;9(6):504-510. doi: 10.1161/CIRCGENETICS.116.001545. Epub 2016 Oct 26.

PubMed [citation]

PMID:: 27784735

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (7)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001339364.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant (also known as p.Lys483Glu in the mature protein) replaces lysine with glutamic acid at codon 504 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A cell-based experimental study has shown that this variant does not disrupt LDL uptake function of the protein (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 25647241; Color internal data). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 27784735). Additionally, this variant has been reported in individuals affected with myocardial infarction (PMID: 25487149). This variant has been identified in 3/251454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422594.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

The p.Lys504Glu variant in LDLR has been reported in 1 Italian and 2 Norwegian individuals with familial hypercholesterolemia (PMID: 25647241, PMID: 15199436), but has been identified in 0.003% (3/113736) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs730882103). This variant has also been reported in ClinVar as having conflicint interpretations of pathogenicity (Variation ID: rs730882103). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003265100.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces lysine with glutamic acid at codon 504 of the LDLR protein (p.Lys504Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs730882103, ExAC 0.008%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15199436, 19318025, 25487149). ClinVar contains an entry for this variant (Variation ID: 183117). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 25647241). 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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