chr19-11113392-C-G

Variant names:

• chr19-11113392-C-G
• rs745343524
• NM_000527.5:c.1301C>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS4 PP1_Strong PM3 PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM3, PP1_Strong, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS4: Variant meets PM2 and is identified in 10 unrelated cases, as follows: 6 patients with DLCN >=6 and 2 patients with Simon-Broome criteria of possible FH from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obesite et des Dyslipidies; 1 case with MedPed criteria from PMID 21868016 (Garcia-Garcia et al., 2011); 1 case with DLCN>6 from PMID 10634824 (Deiana et al., 2000). So PS4 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PM3: Variant meets PM2 and is identified in 2 siblings from PMID 29306853 with childhood total cholesterol levels >700 mg/dL and homozygous for this variant. So PM3 is met. PP1_Strong: Variant segregates with FH phenotype in >1 families, as follows: 6 affected family members from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obesite et des Dyslipidies; 10 affected members tested positive and 7 unaffected members tested negative in one family in 17 informative meiosis from PMID 21868016, so PP1_Strong is met.PP4: Variant meets PM2 and is identified in 10 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585393/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 1.05
• Publications: 12 publications found

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 13 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.
• PM3: 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1301C>G	p.Thr434Arg	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.1301C>G	p.Thr434Arg	missense_variant	Exon 9 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461688 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5 Uncertain:1

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: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subjects mutated among 2600 FH index cases screened = 7 , family members = 4 with unclear co-segregation in 1 family / FH-Sassari-4/Software predictions: Benign -

Oct 28, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM3, PP1_Strong, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS4: Variant meets PM2 and is identified in 10 unrelated cases, as follows: 6 patients with DLCN >=6 and 2 patients with Simon-Broome criteria of possible FH from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obesite et des Dyslipidies; 1 case with MedPed criteria from PMID 21868016 (Garcia-Garcia et al., 2011); 1 case with DLCN>6 from PMID 10634824 (Deiana et al., 2000). So PS4 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM3: Variant meets PM2 and is identified in 2 siblings from PMID 29306853 with childhood total cholesterol levels >700 mg/dL and homozygous for this variant. So PM3 is met. PP1_Strong: Variant segregates with FH phenotype in >1 families, as follows: 6 affected family members from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obesite et des Dyslipidies; 10 affected members tested positive and 7 unaffected members tested negative in one family in 17 informative meiosis from PMID 21868016, so PP1_Strong is met. PP4: Variant meets PM2 and is identified in 10 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: 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:2

Dec 07, 2023

GENinCode PLC

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1301C>G p.(Thr434Arg) missense variant has been reported in >10 FH patients meeting clinical criteria, including patients where secondary causes of high cholesterol were excluded (PS4_STRONG, PP4_SUPPORTING; PMIDs 10634824, 11668640, 11737238, 11810272, ClinGen FH VCEP data). This variant was found to segregate with FH phenotype in >6 informative meioses in >1 family (PP1_STRONG; PMID 21868016, ClinGenVCEP data). This variant is absent from gnomAD v2.1.1 (PM2_MODERATE) and has been observed in the homozygous state in two siblings with a homozygous FH phenotype (PM3_MODERATE; PMID 29306853). Based on the evidence listed above, we have classified this variant as Pathogenic. -

Aug 05, 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.1301C>G (p.Thr434Arg) results in a non-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 was absent in 251382 control chromosomes. c.1301C>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_2000, Fouchier_2001, Garcia-Garcia_2011, Garcia-Garcia_2001, Deina_2000, Albuquerque_2023) and observed to segregate with disease. These data indicate that the variant is very 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. The following publications have been ascertained in the context of this evaluation (PMID: 37813054, 10978268, 10634824, 11810272, 21868016, 11668640). ClinVar contains an entry for this variant (Variation ID: 251774). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;.;.;.;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.0	N;.;.;.;.;N
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.010	D;D;D;D;D;D
Sift4G	Benign	0.090	T;T;T;T;T;T
Polyphen		0.40	B;.;.;.;.;.
Vest4		0.36
MutPred		0.89		Loss of catalytic residue at T434 (P = 0.0094);Loss of catalytic residue at T434 (P = 0.0094);.;.;.;Loss of catalytic residue at T434 (P = 0.0094);
MVP		1.0
MPC		0.67
ClinPred		0.52	D
GERP RS		1.0
Varity_R		0.59
gMVP		0.99
Mutation Taster		=1/99	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

Other links and lift over

dbSNP: rs745343524; hg19: chr19-11224068;