rs730882099

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM5PP2PP3_StrongPP5

The NM_000527.5(LDLR):c.1195G>A(p.Ala399Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A399D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:3O:1

Conservation

PhyloP100: 2.49

Publications

8 publications found

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:

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6886 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000527.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11113287-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226350.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 19-11113286-G-A is Pathogenic according to our data. Variant chr19-11113286-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 183109.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1195G>A	p.Ala399Thr	missense_variant	Exon 9 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1195G>A	p.Ala399Thr	missense_variant	Exon 9 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250750

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460640

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726630

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.0000447

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5116

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111978

Other (OTH)

AF:

0.00

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74226

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:6Uncertain:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

May 22, 2022

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183109). A different missense change at the same codon (p.Ala399Asp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000226350). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant (also known as p.Ala378Thr in the mature protein) replaces alanine with threonine in the type B repeat 1 at codon 399 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). Experimental functional studies for this variant have shown conflicting results. In two different transfected cell assays, this variant showed normal LDLR activity (PMID: 25647241, 32015373). Another study using fibroblasts derived from a homozygous individual affected with a severe phenotype showed a significant reduction in LDL receptor activity (PMID: 16343504). This LDLR variant has been reported in multiple heterozygous individuals affected with familial hypercholesterolemia (PMID: 16250003, 21925044, 23833242, 28502495, 33994402). This variant has also been observed in both compound heterozygous state with a known pathogenic LDLR variant and in homozygosity in several individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 23375686, 27784735, 28432645, 32977124). Additionally, this variant has been reported in an individual affected with myocardial infarction (PMID: 25487149) and in an individual affected with coronary artery disease (PMID: 27050191). This variant has been identified in 5/245772 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 28, 2022

New York Genome Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1195G>A p.(Ala399Thr) variant identified in the LDLR gene substitutes a well conserved Alanine for Threonine at amino acid 399/860 (exon9/18). This variant is found with low frequency in gnomAD(v3.1.2)(1 heterozygote, 0 homozygote; allele frequency: 6.579e-6), suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be deleterious (CADD score = 26.2, REVEL score = 0.755) to the function of the canonical transcript. This variant is reported in ClinVar as Likely Pathogenic (n=3) and as a Variant of Uncertain Significance (n=1) (VarID:183109) and has been reported in many affected individuals in the literature [PMID: 10978268, 15241806, 21925044, others]. Given its presence in many affected individuals in the literature, low frequency in population databases, and in silico predictions of a damaging effect to protein function, the c.1195G>A p.(Ala399Thr) variant identified in the LDLR gene is reported as Likely Pathogenic. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PP3+PS4 -

Familial hypercholesterolemia

Pathogenic:4

Aug 10, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 399 of the LDLR protein (p.Ala399Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypercholesterolemia (PMID: 10634824, 15241806, 16250003, 16343504, 21925044, 23375686, 26723464, 32977124). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 183109). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 32015373). This variant disrupts the p.Ala399 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 21382890), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Apr 29, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with threonine at codon 399 of the LDLR protein. This variant is also known as p.Ala378Thr in the mature protein. This variant alters a conserved alanine residue in the type B repeat 1 of the LDLR protein (a.a. 397-438), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Experimental functional studies for this variant have shown conflicting results. In two different transfected cell assays, this variant showed normal LDLR activity (PMID: 25647241, 32015373). Another study using fibroblasts derived from a homozygous individual affected with a severe phenotype showed a significant reduction in LDL receptor activity (PMID: 16343504). This LDLR variant has been reported in at least nine heterozygous individuals affected with familial hypercholesterolemia (PMID: 16250003, 21925044, 23833242, 28502495, 33994402). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in one individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 23375686); and in homozygous state in two individuals affected with severe homozygous familial hypercholesterolemia (PMID: 23375686, 27784735, 28432645, 32977124). This variant has been identified in 5/245772 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Ala399Asp, is considered to be disease-causing (ClinVar variation ID: 226350), suggesting that alanine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Apr 16, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLR c.1195G>A (p.Ala399Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250750 control chromosomes. c.1195G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Familial Hypercholesterolemia (examples, Bertolini_2013, DErasmo_2017, Sanchez-Hernandez_2016 ). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on LDL-uptake function in a cellular model (Thormaehlen_2015). Additionally, at least one variant at the p.Ala399 residue has been reported as associated with disease (p.Ala399Asp), suggesting that this codon is functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 23375686, 28432645, 27784735, 25647241). ClinVar contains an entry for this variant (Variation ID: 183109). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Uncertain:1Other:1

Jan 30, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in individuals with premature coronary artery disease (CAD) and early myocardial infarction (MI) in the published literature (Anderson et al., 2010; Do et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies show protein expression, receptor binding, and LDL uptake similar to wild type protein (Galicia-Garcia et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as A378T or FH-Nuoro; This variant is associated with the following publications: (PMID: 15241806, 21925044, 10634824, 16250003, 16343504, 20691829, 25647241, 27050191, 27784735, 28502495, 26723464, Giammanco_2022_Abstract, 32977124, 34037665, 35339733, 33994402, 25487149, 32015373, 23375686) -

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance:not provided

Review Status:no classification provided

Collection Method:in vitro

- -

not specified

Pathogenic:1

Oct 21, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been reported in individuals affected with familial hypercholesterolemia (FH) in the published literature (PMIDs: 10634824 (2000), 15241806 (2004), 16250003 (2005), 23375686 (2013), and 26723464 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. A different variant located as the same amino acid posistion has been described as likely pathogenic and pathogenic. Based on the available information, the variant is predicted to be likely pathogenic. -

Cardiovascular phenotype

Uncertain:1

Jun 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A399T variant (also known as c.1195G>A), located in coding exon 9 of the LDLR gene, results from a G to A substitution at nucleotide position 1195. The alanine at codon 399 is replaced by threonine, an amino acid with similar properties, and is located in the EGF precursor-like domain. This variant (also described as p.A378T and FH-Nuoro) has been reported in multiple individuals from a variety of ethnic backgrounds with familial hypercholesterolemia (FH), including heterozygotes, compound heterozygotes, and homozygous cases; it has also been reported in one case and one control from a myocardial infarction cohort (Deiana L et al. Arterioscler. Thromb. Vasc. Biol., 2000 Jan;20:236-43; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510; Chiou KR et al. J Clin Lipidol 2017 Jan;11:386-393.e6). Functional studies in cultured skin fibroblasts have demonstrated conflicting results, with some suggesting reduced LDL receptor activity and others showing no significant difference from wild-type LDL binding and receptor activity (Deiana L et al. Arterioscler. Thromb. Vasc. Biol., 2000 Jan;20:236-43; Pisciotta L et al. Atherosclerosis, 2006 Oct;188:398-405; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Galicia-Garcia U et al. Sci Rep, 2020 02;10:1727). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.;.;.;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

0.58

N;.;.;.;.;N

PhyloP100

2.5

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.8

N;N;N;N;N;N

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0060

D;T;D;D;D;D

Sift4G

Uncertain

0.0080

D;T;D;D;D;D

Polyphen

0.99

D;.;.;.;.;.

Vest4

0.68

MutPred

0.95

Loss of stability (P = 0.1638);Loss of stability (P = 0.1638);.;.;.;Loss of stability (P = 0.1638);

MVP

1.0

MPC

0.33

ClinPred

0.65

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.91

Mutation Taster

=26/74

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over