rs730882100

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_000527.5(LDLR):c.1294C>G(p.Leu432Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,868 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. L432P) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:6O:1

Conservation

PhyloP100: 1.51

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 made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a repeat LDL-receptor class B 1 (size 41) in uniprot entity LDLR_HUMAN there are 61 pathogenic changes around while only 8 benign (88%) in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11113386-T-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

PP5

Variant 19-11113385-C-G is Pathogenic according to our data. Variant chr19-11113385-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 183111.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=4, not_provided=1}. Variant chr19-11113385-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1294C>G	p.Leu432Val	missense_variant	Exon 9 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1294C>G	p.Leu432Val	missense_variant	Exon 9 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

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:

0.000207

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:

251290

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135890

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3Uncertain:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Sep 05, 2022

Institute of Immunology and Genetics Kaiserslautern

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PM2, PM5, PP3, PP5; Variant was found in heterozygous state. Patient also carried NM_000527.5:c.1393T>A heterozygously. -

Dec 01, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Leu411Val in the mature protein) replaces leucine with valine at codon 432 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 has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 10090484, 15199436, 29396260, 35047021). It has also been reported in individuals affected with early-onset myocardial infarction (PMID: 25487149, 25647241) and in individuals affected with coronary artery disease (PMID: 27050191). This variant has been identified in 4/251290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial hypercholesterolemia

Pathogenic:1Uncertain:2

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 432 of the LDLR protein (p.Leu432Val). This variant is present in population databases (rs730882100, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 10090484, 25487149, 25647241, 32770674, 35047021). This variant is also known as L411V. ClinVar contains an entry for this variant (Variation ID: 183111). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Feb 23, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified

Uncertain:1

Sep 06, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1294C>G (p.Leu432Val) results in a conservative amino acid change in the encoded protein sequence. Four 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 251290 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in affected individuals including FH, MI, and CAD, all without strong evidence for causality (i.e. co-segregation data) (Ebhardt_1999, Leren_2004, Do_2015, Thormaehlen_2015, Khera_2016, Rieck_2020, Leren_2021, Rimbert_2022). In addition, LDLR-LOVD, British Heart Foundation classified this variant as likely pathogenic, without evidence to independently evaluate. One published functional study showed that overexpression of p.Leu432Val resulted in intact cellular LDL uptake comparable to wild-type, although authors did list variant as a hypomorphic variant and speculated that the compound heterozygosity of two hypomorphic variants (Y465N and L432V for example) could impair receptor activities in the range of a classic FH-mutant (Thormaehlen_2015). JoJo Genetics noted that variant of interest often co-occured with Y465N (Y444N in legacy name) although the phase was not determined. The following publications have been ascertained in the context of this evaluation (PMID: 20045108, 25487149, 10090484, 27050191, 33740630, 15199436, 32770674, 35047021, 25647241). ClinVar contains an entry for this variant (Variation ID: 183111). Based on the evidence outlined above, the variant was classified as uncertain significance. -

LDLR-related disorder

Uncertain:1

Nov 25, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LDLR c.1294C>G variant is predicted to result in the amino acid substitution p.Leu432Val. This variant has also been reported in individuals with hypercholesterolemia and in controls in different reports (Thormaehlen et al. 2015. PubMed ID: 25647241; Do et al. 2015. PubMed ID: 25487149). It was also found in one individual who harbored the c.1393T>A (p.Tyr465Asn) variant that is also found in this patient, and it was suggested that together the two variants may form a hypomorphic allele, but further studies to confirm they are on the same allele were not performed (Thormaehlen et al. 2015. PubMed ID: 25647241). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant has been reported in ClinVar with interpretations of uncertain significance, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/183111/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L432V variant (also known as c.1294C>G), located in coding exon 9 of the LDLR gene, results from a C to G substitution at nucleotide position 1294. The leucine at codon 432 is replaced by valine, an amino acid with highly similar properties. This variant (also referred to as L411V) has been detected in hypercholesterolemia cohorts, coronary artery disease cohorts, and myocardial infarction cohorts; however, in some cases, clinical detail was limited and/or the variant co-occurred with other variants in the LDLR gene, complicating interpretation of the impact of this variant alone (Ebhardt M et al. Hum. Mutat., 1999;13:257; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Do R et al. Nature, 2015 Feb;518:102-6; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Khera AV et al. J. Am. Coll. Cardiol., 2016 06;67:2578-89; Hartgers ML et al. J Clin Lipidol Dec;12:390-396.e8; Rieck L et al. Clin Genet. 2020 Nov;98(5):457-467; Rimbert A et al. Front Genet. 2021 Jan;12:809256). An in vitro assay reported this variant to be non-disruptive to LDL uptake; however, additional evidence is needed to confirm this finding (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Other:1

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;.;.;.;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Benign

1.3

L;.;.;.;.;L

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.9

D;D;D;D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D

Polyphen

0.95

P;.;.;.;.;.

Vest4

0.37

MutPred

0.90

Loss of stability (P = 0.0371);Loss of stability (P = 0.0371);.;.;.;Loss of stability (P = 0.0371);

MVP

0.99

MPC

0.57

ClinPred

0.82

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.98

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