NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn) AND not provided

Germline classification:: Likely benign (4 submissions)
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:: RCV000162022.18

Allele description [Variation Report for NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn)]

NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn)

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.1024G>A (p.Asp342Asn)

Other names:

NM_000527.5(LDLR):c.1024G>A

HGVS:

NC_000019.10:g.11110735G>A
NG_009060.1:g.26355G>A
NM_000527.5:c.1024G>AMANE SELECT
NM_001195798.2:c.1024G>A
NM_001195799.2:c.901G>A
NM_001195800.2:c.520G>A
NM_001195803.2:c.643G>A
NP_000518.1:p.Asp342Asn
NP_000518.1:p.Asp342Asn
NP_001182727.1:p.Asp342Asn
NP_001182728.1:p.Asp301Asn
NP_001182729.1:p.Asp174Asn
NP_001182732.1:p.Asp215Asn
LRG_274t1:c.1024G>A
LRG_274:g.26355G>A
LRG_274p1:p.Asp342Asn
NC_000019.9:g.11221411G>A
NM_000527.4:c.1024G>A
P01130:p.Asp342Asn
c.1024G>A
p.D342N

Protein change:

D174N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001326; UniProtKB: P01130#VAR_005366

Molecular consequence:

NM_000527.5:c.1024G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1024G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.901G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.520G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.643G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000189625	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	no classification provided (in vitro)	not provided	not applicable	in vitro	PubMed (1) [See all records that cite this PMID]
SCV005209377	Breakthrough Genomics, Breakthrough Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign	germline	not provided	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000189625

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

no classification provided

(in vitro)

not provided

not applicable

in vitro

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

SCV005209377

Breakthrough Genomics, Breakthrough Genomics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign

germline

not provided

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, not provided
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro

Citations

PubMed

Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.

Thormaehlen AS, Schuberth C, Won HH, Blattmann P, Joggerst-Thomalla B, Theiss S, Asselta R, Duga S, Merlini PA, Ardissino D, Lander ES, Gabriel S, Rader DJ, Peloso GM, Pepperkok R, Kathiresan S, Runz H.

PLoS Genet. 2015 Feb;11(2):e1004855. doi: 10.1371/journal.pgen.1004855. Erratum in: PLoS Genet. 2015 Mar 17;11(3):e1005060. doi: 10.1371/journal.pgen.1005060.

PubMed [citation]

PMID:: 25647241
PMCID:: PMC4409815

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

Details of each submission

From Dept. of Genetics and Pharmacogenomics, Merck Research Labs, SCV000189625.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	PubMed (1)

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

From GeneDx, SCV000234648.10

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

Description

The D342N variant in the LDLR gene has been reported previously as a pathogenic variant in association with familial hypercholesterolemia, using alternate nomenclature D321N (Day et al., 1997; Fouchier et al., 2001). While 342N was identified in four patients with early-onset myocardial infarction, it was also identified in 10 control individuals of advanced age with no history of myocardial infarction. Additionally, cholesterol and LDL levels were not reported (Do et al., 2015). The NHLBI ESP Exome Sequencing Project reports that D342N was observed in 27/4406 (0.61%) alleles from individuals of African American background, indicating it may be a rare variant in this population. The D342N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. In addition, in vitro overexpression and complementation experiments suggest that D342N is non-disruptive to LDLR activity (Thormaehlen et al., 2015). A research group recently concluded that there was no definitive evidence for a genotype/phenotype association of D342N with familial hypercholesterolemia (Amendola et al., 2015; Olfson et al., 2015). We interpret D342N as a variant of uncertain significance.

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

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001552212.1

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

Description

The LDLR p.Asp301Asn variant was identified in dbSNP (ID: rs139361635) and in ClinVar (classified benign 2 times, likely benign 2 times, a VUS 4 times and pathogenic once). The variant was also identified in control databases in 168 of 282430 chromosomes (3 homozygous) at a frequency of 0.000595 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 160 of 24944 chromosomes (freq: 0.006414), Latino in 6 of 35432 chromosomes (freq: 0.000169), Other in 1 of 7220 chromosomes (freq: 0.000139) and European (non-Finnish) in 1 of 128970 chromosomes (freq: 0.000008), but not in the Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The D301N variant in LDLR has been reported in 4 individuals with possible or definitive hypercholesterolemia (Do_1997_PMID:25487149; Fouchier_2001_PMID:11810272; Sjouke_2015_PMID:24585268; Leigh_2008_PMID:18325082). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asp301 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. 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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Breakthrough Genomics, Breakthrough Genomics, SCV005209377.1

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

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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000234648	GeneDx	flagged submission Reason: Conflicts with expert reviewed submission without evidence to support different classification Notes: None (GeneDx Variant Classification (06012015))	Uncertain significance (Feb 4, 2016)	germline	clinical testing	Citation Link,
SCV001552212	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	flagged submission Reason: Conflicts with expert reviewed submission without evidence to support different classification Notes: None	Uncertain significance	unknown	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000234648

GeneDx

flagged submission

Reason: Conflicts with expert reviewed submission without evidence to support different classification

Notes: None

(GeneDx Variant Classification (06012015))

Uncertain significance
(Feb 4, 2016)

germline

clinical testing

Citation Link,

SCV001552212

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

flagged submission

Reason: Conflicts with expert reviewed submission without evidence to support different classification

Notes: None

Uncertain significance

unknown

clinical testing

Last Updated: Oct 26, 2024

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