rs778284147

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 3P and 4B. BS3PM2PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.139G>A (p.Asp47Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (BS3, PM2 and PP4) 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: BS3 - Level 1 assays: PMID 30413722: Heterologous cells (CHO-ldlA7), FACS and western blot assays - result - Normal (>90%) expression, binding and uptake ---- whole cycle is above 90% of wild-type activity, so BS3 is Met.PM2 - PopMax MAF = 0.0001307 (0.013%) in South Asian exomes (gnomAD v2.1.1).PP4 - Variant meets PM2. Identified in at least 1 FH case from Laboratory of Genetics and Molecular Cardiology who fulfill Simon-Broome criteria. LINK:https://erepo.genome.network/evrepo/ui/classification/CA041918/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:5U:7

Conservation

PhyloP100: 9.48

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 Uncertain_significance. Variant got -1 ACMG points.

PM2

PP4

BS3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.139G>A	p.Asp47Asn	missense_variant	2/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.139G>A	p.Asp47Asn	missense_variant	2/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251226

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461622

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3Uncertain:5

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 07, 2021	The NM_000527.5(LDLR):c.139G>A (p.Asp47Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (BS3, PM2 and PP4) 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: BS3 - Level 1 assays: PMID 30413722: Heterologous cells (CHO-ldlA7), FACS and western blot assays - result - Normal (>90%) expression, binding and uptake ---- whole cycle is above 90% of wild-type activity, so BS3 is Met. PM2 - PopMax MAF = 0.0001307 (0.013%) in South Asian exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in at least 1 FH case from Laboratory of Genetics and Molecular Cardiology who fulfill Simon-Broome criteria. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant (also known as p.Asp26Asn in the mature protein, and as FH Hyogo) replaces aspartic acid with asparagine in the first LDLR-A repeat in codon 47 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). A functional study reported that this variant does not cause a defect in LDLR expression and function (PMID: 30413722). This LDLR variant has been reported in over 15 heterozygous individuals affected with familial hypercholesterolemia (PMID 11313767, 11857755, 18718593, 29399563, 32331935, 33547002, 33533259, 35319679, 35929461; communication with an external laboratory; ClinVar variation ID: 251034). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 35319679). It has been shown that this variant segregates with disease in 6 affected individuals from two unrelated families (communication with an external laboratory; ClinVar variation ID: 251034); some individuals carrying this variant did not show elevated cholesterol levels, reflecting incomplete penetrance. This variant has been identified in 4/251226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2022	- -
Uncertain significance, 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 / FH-Hyogo / Software predictions: Damaging -
Uncertain significance, no assertion criteria provided	research	Iberoamerican FH Network	Mar 01, 2016	- -

Familial hypercholesterolemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 10, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 47 of the LDLR protein (p.Asp47Asn). This variant is present in population databases (rs778284147, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11313767, 11857755, 18718593, 29399563, 33547002; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as D26N. ClinVar contains an entry for this variant (Variation ID: 251034). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 30413722). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 13, 2023	This missense variant (also known as p.Asp26Asn in the mature protein, and as FH Hyogo) replaces aspartic acid with asparagine in the first LDLR-A repeat in codon 47 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). A functional study reported that this variant does not cause a defect in LDLR expression and function (PMID: 30413722). This LDLR variant has been reported in over 15 heterozygous individuals affected with familial hypercholesterolemia (PMID 11313767, 11857755, 18718593, 29399563, 32331935, 33547002, 33533259, 35319679, 35929461; communication with an external laboratory; ClinVar variation ID: 251034). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 35319679). It has been shown that this variant segregates with disease in 6 affected individuals from two unrelated families (communication with an external laboratory; ClinVar variation ID: 251034); some individuals carrying this variant did not show elevated cholesterol levels, reflecting incomplete penetrance. This variant has been identified in 4/251226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Functional studies with transfected CHO-IDlA7 cells showed similar binding and update as the wild-type (Benito-Vicente et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D26N) and FH Hyogo; This variant is associated with the following publications: (PMID: 18718593, 33547002, 32331935, 11313767, 9399845, 29399563, 11857755, 25911080, 30413722, 31491741) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

The c.139G>A (p.D47N) alteration is located in coding exon 2 of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 139, causing the aspartic acid (D) at amino acid position 47 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (4/251226) total alleles studied. The highest observed frequency was 0.01% (4/30614) of South Asian alleles. This alteration has been reported in several familial hypercholesterolemia (FH) cohorts (Varret, 1998; Heath, 2001; Bunn, 2002; Miyake, 2009; Kim, 2018). It has also been detected in the heterozygous state in an individual diagnosed with homozygous FH, though no second variant was identified (Huang, 2015). This amino acid position is highly conserved in available vertebrate species. Functional studies suggest that this alteration does not impact protein function (Benito-Vicente, 2018). This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

M;.;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-4.5

D;D;D;D;D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

D;D;D;D;T;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.90

MutPred

0.95

Loss of ubiquitination at K43 (P = 0.0997);Loss of ubiquitination at K43 (P = 0.0997);Loss of ubiquitination at K43 (P = 0.0997);Loss of ubiquitination at K43 (P = 0.0997);Loss of ubiquitination at K43 (P = 0.0997);Loss of ubiquitination at K43 (P = 0.0997);

MVP

1.0

MPC

0.80

ClinPred

0.92

GERP RS

5.4

Varity_R

0.68

gMVP

1.0

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