chr19-11113292-C-G

Variant names:

• chr19-11113292-C-G
• rs146200173
• NM_000527.5:c.1201C>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS1_Moderate PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000527.5(LDLR):​c.1201C>G​(p.Leu401Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,062 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L401H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:3
• Conservation: PhyloP100: 7.81

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]

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]

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS1: Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000527.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11113292-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2921174.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.909
• PP5: Variant 19-11113292-C-G is Pathogenic according to our data. Variant chr19-11113292-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113292-C-G is described in Lovd as [Pathogenic]. Variant chr19-11113292-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	c.1201C>G	p.Leu401Val	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	c.1201C>G	p.Leu401Val	missense_variant	Exon 9 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152098 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.00000797 AC: 2 AN: 250924 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460964 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726802

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33464

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44720

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86224

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53080

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1112002

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152098 Hom.: 0 Cov.: 29 AF XY: 0.000108 AC XY: 8 AN XY: 74298

Gnomad4 AFR AF: 0.000217 AC: 0.000217255 AN: 0.000217255

Gnomad4 AMR AF: 0.0000657 AC: 0.0000656685 AN: 0.0000656685

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.000014702 AN: 0.000014702

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000252 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6 Uncertain:3

May 11, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1201C>G (p.Leu401Val) variant in the LDLR gene has been observed in multiple individuals with familial hypercholesteromeia (PMID: 9104431, 21722902, 25461735). In addition, a missense variant at the same residue, p.Leu401His, has been previously reported in other affected individuals (PMID: 7573037, 11810272,15701167). Therefore, this variant in the LDLR gene is classified as likely pathogenic. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 01, 2016

Iberoamerican FH Network

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1 compound heterozygous on LDL Apheresis /FH-Norvege / Software predictions: Conflicting -

Nov 14, 2023

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.Leu380Val in the mature protein) replaces leucine with valine at codon 401 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071) and segregated with disease in multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 06, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Moderate, PM2, PM5_Supporting, PP3 -

Aug 31, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial hypercholesterolemia Pathogenic:4

Apr 28, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.1201C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant is found in 2/119858 control chromosomes at a frequency of 0.0000167, which does not exceed maximal expected frequency of a pathogenic allele (0.0012508) to exclude pathogenicity. The variant was reported in several FH patients and one study reported the variant to co-segregate with hypercholesterolemia (Leren_JIM_19970) indicating pathogenicity. In addition, a clinical laboratory and a reputable database classify this variant as Likely pathogenic / Disease causing. Taken together, this variant was classified as Pathogenic. -

Jan 30, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 401 of the LDLR protein. This variant is also known as p.Leu380Val in the mature protein. This variant alters a conserved leucine residue in the LDLR 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. To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 40 heterozygous individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071, 33740630, 34037665; Color internal data). 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: 36325061). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Leu401His, is considered to be disease-causing (ClinVar variation ID: 3735), suggesting that leucine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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 401 of the LDLR protein (p.Leu401Val). This variant is present in population databases (rs146200173, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9104431, 12124988, 21722902, 24507775, 25461735). 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. This variant is also known as p.Leu380Val. ClinVar contains an entry for this variant (Variation ID: 161267). 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%. This variant disrupts the p.Leu401 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7573037, 11810272, 15701167, 19843101). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jan 22, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:3

Feb 20, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in individuals with a history of early-onset myocardial infarction (PMID: 30586733); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L380V); This variant is associated with the following publications: (PMID: 12124988, 25461735, 32041611, 32715071, 33740630, 25637381, 23669246, 21722902, 24507775, 23833242, 31447099, 34037665, 34040191, 33955087, 22683370, 21957200, 9104431, 30586733) -

Nov 02, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1201C>G (p.Leu401Val) variant has been reported in the published literature in individuals with familial hypercholesterolemia (FH) (PMID: 9104431 (1997), 21722902 (2011), 25461735 (2015), 32715071(2020), 34037665 (2021), 33740630 (2021)). The frequency of this variant in the general population, 0.0002 (5/24928 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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 damaging. Based on the available information, this variant is classified as likely pathogenic. -

Dyslipidemia Pathogenic:1

Dec 30, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiovascular phenotype Pathogenic:1

Jul 16, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L401V variant (also known as c.1201C>G), located in coding exon 9 of the LDLR gene, results from a C to G substitution at nucleotide position 1201. The leucine at codon 401 is replaced by valine, an amino acid with highly similar properties. This alteration, also referred to as L380V, has been reported in hypercholesterolemia and early onset myocardial infarction cohorts (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Lange LA et al. Am. J. Hum. Genet., 2014 Feb;94:233-45; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Khera AV et al. Circulation, 2019 03;139:1593-1602). This alteration was also described to segregate with the disease (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94). This variant has been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;.;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.5	L;.;.;.;.;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		0.50	P;.;.;.;.;.
Vest4		0.65
MVP		1.0
MPC		0.59
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs146200173; hg19: chr19-11223968;