rs368562025

Positions:

chr19-11113329-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS4_ModeratePM2PP1PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1238C>T (p.Thr413Met) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Moderate, PP1 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: PM2 - PopMax MAF = 0.00006533 (0.007%) in South Asian (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 6 index cases.PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from GeneDx laboratory.PP4 - Variant meets PM2. Variant identified in 6 index cases (2 cases from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with DLCN criteria, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023439/MONDO:0007750/013

Frequency

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

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

LDLR
ENST00000558518.6 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:19U:3

Conservation

PhyloP100: 1.71

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 Likely_pathogenic. Variant got 6 ACMG points.

PS4

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

PM2

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

PP1

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

PP4

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.1238C>T	p.Thr413Met	missense_variant	9/18	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.1238C>T	p.Thr413Met	missense_variant	9/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152072

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:

0.0000279

AC:

AN:

251176

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135870

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:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461564

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

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

Alfa

AF:

0.0000669

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:19Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:10Uncertain:2

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 23, 2021	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2015	MAF =<0.3%, likely pathogenic based on the integrative in-silico score, previously reported as P/LP in the literature -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4_Moderate+PM3+PP4+PS3_Supporting -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 09, 2021	NM_000527.5(LDLR):c.1238C>T (p.Thr413Met) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Moderate, PP1 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: PM2 - PopMax MAF = 0.00006533 (0.007%) in South Asian (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 6 index cases. PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from GeneDx laboratory. PP4 - Variant meets PM2. Variant identified in 6 index cases (2 cases from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with DLCN criteria, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria). -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 31, 2024	This missense variant replaces threonine with methionine at codon 413 in the LDLR type B repeat 1 of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Thr392Met in the mature protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have indicated no significant change in LDLR protein expression and function due to this variant (PMID: 32015373, 34029164). This variant has been reported in over twenty heterozygous individuals affected with familial hypercholesterolemia (PMID: 11668627, 11857755, 15015036, 15199436, 15576851, 17539906, 19843101, 22883975, 25682026, 31993549; ClinVar SCV001960926.1) and in an individual affected with myocardial infarction (PMID: 25487149). This variant has been observed in an individual with severe familial hypercholesterolemia who also carried a pathogenic truncation variant in the same gene (PMID: 34029164). This variant has been reported to segregate with disease in two members of a family (ClinVar SCV001960926.1). This variant has been identified in 7/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 05, 2008	- -
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 / Software predictions: Conflicting -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Jan 03, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 08, 2023	Criteria applied: PS4_MOD,PM2_SUP,PP1,PP3,PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 23, 2017	This c.1238C>T (p.Thr413Met) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 11857755, 17539906, 19843101, 11668627, 15015036, 25682026) or myocardial infarction (PMID: 25487149). The p.Thr413Met variant occurs within the low-density lipoprotein receptor repeat class B domain of the LDLR protein (https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi?seqinput=NP_001182729.1 ). The c.1238C>T variant is rare in the general population and threonine at position 413 of the LDLR protein is highly evolutionarily conserved. The c.1238C>T (p.Thr413Met) variant in the LDLR gene is classified as likely pathogenic. -

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24055113, 25487149, 11668627, 11857755, 25637381, 15015036, 15576851, 15199436, 17539906, 28145427, 32015373, 32719484, 32522009, 30586733, 31447099, 34037665, 25682026, 27783906, 22883975, 35913489, 33854068, 34906840, Gratton2023[CaseReport], 37409534, 35460704, 37443404, 38740897, 38258479, 38506081) -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	The LDLR c.1238C>T; p.Thr413Met variant (rs368562025) is reported in the literature in multiple individuals affected with familial hypercholesterolemia and myocardial infarction (Do 2015, Dong 2022, eMERGE Consortium 2019, Sturm 2021, Sustar 2022). This variant is also reported as likely pathogenic by an expert panel in ClinVar (Variation ID: 161276). This variant is found in the general population with an overall allele frequency of 0.003% (7/251176 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.692). Based on available information, this variant is considered to be likely pathogenic. References: Do R, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015 Feb 5;518(7537):102-6. PMID: 25487149. Dong W et al. Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia. J Lipid Res. 2022 Jun;63(6):100209. PMID: 35460704. eMERGE Consortium et al. Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. Am J Hum Genet. 2019 Sep 5;105(3):588-605. PMID: 31447099. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665. Sustar U et al. Universal screening for familial hypercholesterolemia in 2 populations. Genet Med. 2022 Oct;24(10):2103-2111. PMID: 35913489. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 25, 2024	PP1, PP4, PM2, PS3_supporting, PS4_moderate -

Familial hypercholesterolemia

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2023	This missense variant (also known as p.Thr392Met in the mature protein) replaces threonine with methionine at codon 413 in the LDLR type B repeat 1 of the EGF precursor homology domain of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have indicated no significant change in LDLR protein expression and function due to this variant (PMID: 32015373, 34029164). This variant has been reported in over twenty heterozygous individuals affected with familial hypercholesterolemia (PMID: 11668627, 11857755, 15015036, 15199436, 15576851, 17539906, 19843101, 22883975, 25682026, 31993549, 34037665; ClinVar SCV001960926.1). It has also been reported in an individual affected with myocardial infarction (PMID: 25487149) and in an individual affected with low circulating HDL-C (PMID: 35460704). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 34029164). This variant has been reported to segregate with disease in two members of a family (ClinVar SCV001960926.1). This variant has been identified in 7/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2022	Variant summary: LDLR c.1238C>T (p.Thr413Met) results in a non-conservative amino acid change located in the EGF spacer domain (Dong_2022) of 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 2.8e-05 in 253468 control chromosomes (gnomAD and publication data). c.1238C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia, Myocardial infarction or Coronary artery disease (Bunn_2022, Leren_2004, Taylor_2007, Hooper_2012, Do_2014, Khera_2016, Wald_2016, Saadatagah_2021, Sturm_2021). These data indicate that the variant is likely to be associated with disease. At least one functional study showed LDLR activity (LDL binding and uptake) of this variant determined by flow cytometry and indicated LDL uptake as 85% WT and LDL binding as 80% WT, but no effect on protein expression level in transfected cellls (Galicia-Garcia_2020). Twelve ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=3), likely pathogenic (n=8) and pathogenic (n=1), including one expert panel (ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel) classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 413 of the LDLR protein (p.Thr413Met). This variant is present in population databases (rs368562025, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 11857755, 20236128, 25682026; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 161276). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 13, 2020	- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2023

The p.T413M variant (also known as c.1238C>T), located in coding exon 9 of the LDLR gene, results from a C to T substitution at nucleotide position 1238. The threonine at codon 413 is replaced by methionine, an amino acid with similar properties. This variant (also described as p.T392M) has been detected in individuals with familial hypercholesterolemia (FH); however, clinical details were limited in most cases (Bunn CF et al. Hum. Mutat., 2002 Mar;19:311; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Taylor A et al. Clin. Genet., 2007 Jun;71:561-8; Safarova MS et al. Eur. J. Hum. Genet., 2017 04;25:410-415). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Do R et al. Nature, 2015 Feb;518:102-6). This alteration was also detected in one control subject from a myocardial infarction study (Khera AV et al. Circulation, 2019 03;139:1593-1602). This alteration has also been reported in additional subjects with FH and as a compound heterozygote in a child with features of FH (personal communication). This amino acid position is well 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. -

Hypercholesterolemia

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.;.;.;.;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

1.5

L;.;.;.;.;L

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.8

D;D;D;D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.023

D;D;D;D;D;D

Sift4G

Uncertain

0.027

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.65

MVP

1.0

MPC

0.80

ClinPred

0.78

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

gMVP

0.96

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