NM_000527.5(LDLR):c.1516G>A (p.Val506Met) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Feb 23, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000237901.13

Allele description [Variation Report for NM_000527.5(LDLR):c.1516G>A (p.Val506Met)]

NM_000527.5(LDLR):c.1516G>A (p.Val506Met)

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.1516G>A (p.Val506Met)

Other names:

NM_000527.5(LDLR):c.1516G>A; p.Val506Met

HGVS:

NC_000019.10:g.11113692G>A
NG_009060.1:g.29312G>A
NM_000527.5:c.1516G>AMANE SELECT
NM_001195798.2:c.1516G>A
NM_001195799.2:c.1393G>A
NM_001195800.2:c.1012G>A
NM_001195803.2:c.1135G>A
NP_000518.1:p.Val506Met
NP_000518.1:p.Val506Met
NP_001182727.1:p.Val506Met
NP_001182728.1:p.Val465Met
NP_001182729.1:p.Val338Met
NP_001182732.1:p.Val379Met
LRG_274t1:c.1516G>A
LRG_274:g.29312G>A
LRG_274p1:p.Val506Met
NC_000019.9:g.11224368G>A
NM_000527.4:c.1516G>A
c.1516G>A

Protein change:

V338M

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000209; dbSNP: rs373848925

NCBI 1000 Genomes Browser:

rs373848925

Molecular consequence:

NM_000527.5:c.1516G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1516G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1393G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1012G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1135G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295479	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely benign (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000606447	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV004822469	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20145306, 25487149, 32770674, 25741868
SCV005328519	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain Significance (Feb 23, 2024)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	7	not provided	not provided	108544	not provided	clinical testing, research, curation
not provided	germline	yes	1	not provided	not provided	1	not provided	literature only

Citations

PubMed

Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.

Chmara M, Wasag B, Zuk M, Kubalska J, Wegrzyn A, Bednarska-Makaruk M, Pronicka E, Wehr H, Defesche JC, Rynkiewicz A, Limon J.

J Appl Genet. 2010;51(1):95-106. doi: 10.1007/BF03195716.

PubMed [citation]

PMID:: 20145306

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

Do R, Stitziel NO, Won HH, Jørgensen AB, Duga S, Angelica Merlini P, Kiezun A, Farrall M, Goel A, Zuk O, Guella I, Asselta R, Lange LA, Peloso GM, Auer PL; NHLBI Exome Sequencing Project., Girelli D, Martinelli N, Farlow DN, DePristo MA, Roberts R, Stewart AF, et al.

Nature. 2015 Feb 5;518(7537):102-6. doi: 10.1038/nature13917. Epub 2014 Dec 10.

PubMed [citation]

PMID:: 25487149
PMCID:: PMC4319990

See all PubMed Citations (4)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295479.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606447.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	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 All of Us Research Program, National Institutes of Health, SCV004822469.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant (also known as p.Val485Met in the mature protein) replaces valine with methionine at codon 506 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia, who also carried a large duplication variant encompassing LDLR exons 3-12 (PMID: 20145306). This variant has also been reported in another individual affected with familial hypercholesterolemia (PMID: 32770674) and in an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has been identified in 16/251450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary 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	108544	not provided	not provided		7	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV005328519.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000527.5(LDLR):c.1516G>A (p.Val506Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PP3: REVEL=0.757.

#	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: Oct 8, 2024

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