rs139361635

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.005579 (0.56%) in African exomes (gnomAD v2.1.1). It is above 0.5%, so BA1 is met.BP4 - REVEL = 0.283. it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. Variant is not predicted to alter splicing, so BP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023404/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 3 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:5B:9O:1

Conservation

PhyloP100: 0.471

Variant links:

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1024G>A	p.Asp342Asn	missense_variant	7/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1024G>A	p.Asp342Asn	missense_variant	7/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

243

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00550

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000454

AC:

114

AN:

251038

Hom.:

AF XY:

0.000331

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.00659

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000165

AC:

241

AN:

1461476

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

109

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.00574

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.00160

AC:

243

AN:

152298

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00548

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000953

Hom.:

Bravo

AF:

0.00189

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000651

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:5Benign:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, flagged submission	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, flagged submission	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?) / Software predictions: Benign -
Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Dec 13, 2021	The NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.005579 (0.56%) in African exomes (gnomAD v2.1.1). It is above 0.5%, so BA1 is met. BP4 - REVEL = 0.283. it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. Variant is not predicted to alter splicing, so BP4 is met. -

not provided

Uncertain:2Benign:1Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, flagged submission	clinical testing	GeneDx	Feb 04, 2016	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. -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Uncertain significance, flagged submission	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 19, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 29, 2021	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. -

Familial hypercholesterolemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 11, 2018	- -

Hypercholesterolemia

Uncertain:1

Uncertain significance, flagged submission

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

8.3

DANN

Benign

0.97

DEOGEN2

Uncertain

0.58

D;.;.;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.76

T;T;T;T;T;T

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.043

T;T;T;T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.16

N;.;.;.;.;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.96

N;N;N;N;N;N

REVEL

Benign

0.28

Sift

Benign

0.34

T;T;T;T;T;T

Sift4G

Benign

0.13

T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;.;.

Vest4

0.19

MVP

1.0

MPC

0.21

ClinPred

0.0055

GERP RS

-0.69

Varity_R

0.22

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over