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

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 29, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000218676.18

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)

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000271916	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 19, 2016)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 26332594, 9259195, 18325082, 24055113, 25637381, 25487149, 11810272, 24585268, 24033266
SCV001431979	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Nov 29, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9259195, 18325082, 24055113, 25637381, 25487149, 30583242 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000271916

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 19, 2016)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001431979

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Nov 29, 2021)

germline

clinical testing

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	not provided	2	2	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of Medically Actionable Secondary Findings in the 1000 Genomes.

Olfson E, Cottrell CE, Davidson NO, Gurnett CA, Heusel JW, Stitziel NO, Chen LS, Hartz S, Nagarajan R, Saccone NL, Bierut LJ.

PLoS One. 2015;10(9):e0135193. doi: 10.1371/journal.pone.0135193.

PubMed [citation]

PMID:: 26332594
PMCID:: PMC4558085

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 (10)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271916.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (9)

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Asp342Asn var iant in LDLR has been reported in 3 individuals with possible or definitive hype rcholesterolemia (Do 1997, Fouchier 2001, Sjouke 2015), including in one individ ual with a second LDLR variant. However, this variant has also been identified i n 0.6% (160/24944) of African chromosomes by the Genome Aggregation Consortium ( gnomAD, http://exac.broadinstitute.org). Computational prediction tools and cons ervation analysis suggest that the variant may not impact the protein, though th is information is not predictive enough to rule out pathogenicity. In summary, w hile the clinical significance of the p.Asp342Asn variant is uncertain, its freq uency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: P S4_Supporting, BS1, BP4.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001431979.2

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

Description

Variant summary: LDLR c.1024G>A (p.Asp342Asn) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 292610 control chromosomes, predominantly at a frequency of 0.0064 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1024G>A has been reported in the literature in individuals with hypercholesterolemia, however it was also found in healthy controls (e.g. Do_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated normal activities for this variant (Guo_2019). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and reported the variant with conflicting assessments (i.e. VUS (n=3), likely benign (n=3) / benign (n=2)). Based on the evidence outlined above, the variant was classified as benign.

#	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 26, 2024

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