rs137929307

Positions:

chr19-11116928-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS4PP1_StrongPM2PP3PP4PS3_Moderate

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PS3_Moderate, PP3 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: PS4 - Variant meets PM2. Variant identified in 239 index cases.PP1_strong - 130 informative meioses (1 from Robarts Research Institute; 83 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 19 from Laboratory of Genetics and Molecular Cardiology; 2 from University of British Columbia; 25 from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).PM2 - PopMax MAF = 0.0001161 (0.012%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay - PMID:21865347 - study on hmz patient's lymphocytes, FACS, LDLR activity value range: 39-53%.PP3 - REVEL: 0,938. PP4 - Variant meets PM2. Variant identified in 239 index cases fulfill specific clinical criteria for FH (3 cases with Simon-Broome from Color laboratory; 189 cases with MedPed criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 5 cases with Simon-Broome criteria from GeneDx; 15 cases with Siom-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 2 cases with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 6 cases with DLCN criteria from University of British Columbia; 19 cases with Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023577/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 2 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:43O:1

Conservation

PhyloP100: 8.01

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 Pathogenic. Variant got 14 ACMG points.

PS3

PS4

PM2

PP1

PP3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1775G>A	p.Gly592Glu	missense_variant	12/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1775G>A	p.Gly592Glu	missense_variant	12/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152078

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:

0.0000735

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251486

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135916

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74254

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000960

Alfa

AF:

0.0000828

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:43Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:25

Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Likely pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/220 non-FH alleles; 0/77 healthy control individuals -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 22, 2024	Criteria applied: PS4,PP1_STR,PS3_MOD,PM2,PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Sep 07, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 09, 2021	NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PS3_Moderate, PP3 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: PS4 - Variant meets PM2. Variant identified in 239 index cases. PP1_strong - 130 informative meioses (1 from Robarts Research Institute; 83 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 19 from Laboratory of Genetics and Molecular Cardiology; 2 from University of British Columbia; 25 from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PM2 - PopMax MAF = 0.0001161 (0.012%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay - PMID:21865347 - study on hmz patient's lymphocytes, FACS, LDLR activity value range: 39-53%. PP3 - REVEL: 0,938. PP4 - Variant meets PM2. Variant identified in 239 index cases fulfill specific clinical criteria for FH (3 cases with Simon-Broome from Color laboratory; 189 cases with MedPed criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 5 cases with Simon-Broome criteria from GeneDx; 15 cases with Siom-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 2 cases with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 6 cases with DLCN criteria from University of British Columbia; 19 cases with Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Mar 03, 2019	- -
Likely pathogenic, 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	- -
Likely pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	UCSF Pediatric Lipid Clinic, University of California, San Francisco	-	The p.G592E variant in LDLR segregates with elevated level of LDL-C in a family of over ten individuals. The allele frequency of this variant in the population is 0.00004 based on the GnomAD database. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Oct 29, 2018	This nucleotide substitution causes an exchange of the amino acid of glycine (Gly) to glutamic acid (Glu) p.Gly592Glu (legacy name: p.Gly571Glu). This change has already been described in the literature as FH Sicily, FH Foggia 1 and FH Naples 4 and has been found in patients with familial hypercholesterolemia and is associated with elevated cholesterol and LDL-C levels. It results in a reduced amount of biologically active LDL receptors on the cell surface. We observed this variant in a patient with TC up to 350 mg/dl and LDL-C approx 290 mg/dl at the age of 48 and in a patient with TC up to 300 mg/dl and LDL-C approx 250 mg/dl at the age of 5. PMID: 1301956, 27998977, 22390909, 26036859. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 29, 2021	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 27, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 04, 2024	This missense variant (also known as p.Gly571Glu in the mature protein and as FH-Sicily, FH Foggia-1, FH Naples) is located in the fifth LDLR type B repeat 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). A functional study has shown that this variant results in a partial loss of LDLR activity (PMID: 21865347). The variant has been identified in over 200 heterozygous and homozygous familial hypercholesterolemia patients from multiple European ethnicities (PMID: 1301956, 9654205, 11139254, 11139254, 11317361, 11641914, 11754108, 15199436, 15241806, 17765246, 18263977, 20145306, 20663204, 21310417, 21925044, 22698793, 23375686, 25461735, 25463123, 25487149, 26020417, 31947532, 35741760). This variant is highly recurrent in Slovakia, Czech Republic, and Poland (PMID: 26238499). A different variant occurring at the same codon, p.Gly592Arg, is a likely pathogenic mutation (Clinvar variation ID: 373769), indicating that glycine at this position is important for LDLR protein function. This variant has been identified in 16/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Institute for Integrative and Experimental Genomics, University of Luebeck	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes. -
Pathogenic, criteria provided, single submitter	research	Laan Lab, Human Genetics Research Group, University of Tartu	May 01, 2021	- -

not provided

Pathogenic:8Other:1

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2023	Published functional studies demonstrate that G592E results in reduced LDL receptor activity (Hobbs et al., 1992); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.G571E, FH Sicily, FH Foggi, FH Naples-4; This variant is associated with the following publications: (PMID: 27998977, 11524740, 24627126, 25282520, 34167030, 32423031, 35339733, 34697415, 21310417, 15864114, 26238499, 11641914, 22390909, 25637381, 21865347, 20145306, 26036859, 20663204, 15523646, 11848618, 26666465, 27824480, 21382890, 27050191, 19062533, 27578104, 25463123, 27784735, 22294733, 22698793, 26020417, 26892515, 15890894, 23833242, 18263977, 25487149, 16627557, 25936317, 23375686, 24507775, 26723464, 28965616, 15241806, 19026292, 17539906, 9654205, 17196209, 11139254, 20506408, 11754108, 11317361, 31617323, 31447099, 21925044, 33975813, 33303402, 32719484, 32660911, 33269076, 32770674, 32977124, 31589614, 32041611, 33740630, 33418990, 34037665, 34456049, 32009526, 35741760, 35913489, 33955087, 30710474, 1301956) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LDLR: PP1:Strong, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 08, 2022	Internal analysis revealed that the variant was statistically enriched in familial hypercholesterolemia cases over matched controls in the published literature (PMID: 17765246 (2008), 20145306 (2010), 21925044 (2011), 22698793 (2012), and 23375686 (2013)). Additionally, reduced LDL receptor activity was observed from fibroblasts and peripheral blood T-lymphocytes extracted from patients with this variant ((PMID: 1301956 (1992) and 21865347 (2011)). -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 02, 2022	PP1_strong, PP3, PP4, PM2, PS3, PS4 -

Familial hypercholesterolemia

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2024	This missense variant replaces glycine with glutamic acid at codon 592 in the fifth LDLR type B repeat of the LDLR protein. This variant is also known as p.Gly571Glu in the mature protein and as FH-Sicily, FH Foggia-1, FH Naples. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant results in a partial loss of LDLR activity (PMID: 21865347). The variant has been identified in over 200 heterozygous and homozygous familial hypercholesterolemia patients from multiple European ethnicities (PMID: 1301956, 9654205, 11139254, 11139254, 11317361, 11641914, 11754108, 15199436, 15241806, 17765246, 18263977, 20145306, 20663204, 21310417, 21925044, 22698793, 23375686, 25461735, 25463123, 25487149, 26020417, 31947532, 35741760). This variant is highly recurrent in Slovakia, Czech Republic, and Poland (PMID: 26238499). A different variant occurring at the same codon, p.Gly592Arg, is a likely pathogenic mutation (Clinvar variation ID: 373769), indicating that glycine at this position is important for LDLR protein function. This variant has been identified in 16/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 592 of the LDLR protein (p.Gly592Glu). This variant is present in population databases (rs137929307, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15864114, 20663204, 21310417). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 21925044, 23375686, 26238499). This variant is also known as p.Gly571Glu. ClinVar contains an entry for this variant (Variation ID: 161271). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 13, 2016	Variant summary: The LDLR c.1775G>A (p.Gly592Glu) variant involves the alteration of a conserved nucleotide. Gly592 is highly conserved across species, and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 6/121608 control chromosomes at a frequency of 0.0000493, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). This variant has been reported in many FH patients in both heterozygous, compound heterozygous, and homozygous states with evidence of co-segregation in some of the families. Functional studies indicate that the variant of interest has defective LDL receptor activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	-	- -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 04, 2020

The p.Gly592Glu variant in LDLR has been reported in >200 Caucasian individuals with familial hypercholesterolemia (FH) and segregated with disease in >30 affected relatives from >3 families (Gorski 1998 PMID: 9654205, Miltiadous 2001 PMID: 11317361, Kuhrova 2002 PMID: 11754108, Kublaska 2008 PMID: 18263977, Bourbon 2008 PMID: 17765246, Chmara 2010 PMID: 20145306, Diakou 2011 PMID: 21925044, Tichy 2012 PMID: 22698793, Bertolini 2013 PMID: 23375686, Do 2015 PMID: 25487149, Medeiros 2015 PMID: 26020417, Jannes 2015 PMID: 25461735, Braenne 2015 PMID: 26036859). This variant has also been identified in 0.01% (15/129176) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of FH in the general population. Furthermore, in vitro functional studies support that the p.Gly592Glu variant may impact protein function (Romano 2011 PMID: 21865347). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in multiple affected individuals and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Supporting. -

Syndromic X-linked intellectual disability Najm type

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

not provided

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

- -

Hypercholesterolemia

Pathogenic:1

Pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 15, 2021

ACMG categories: PS3,PM1,PP1,PP3,PP4,PP5 -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2021

The p.G592E pathogenic mutation (also known as c.1775G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1775. The glycine at codon 592 is replaced by glutamic acid, an amino acid with some similar properties, and is located in the EGF precursor-like domain. This mutation, also known as FH-Sicily and G571E, has been detected in many unrelated individuals with familial hypercholesterolemia (FH), and has also been reported to impact protein function (Hobbs et al. Hum Mutat. 1992;1(6):445-66; Miltiadous G et al. Hum Mutat. 2001;17(5):432-3; Romano M et al. J Lipid Res. 2011;52(11):2095-100; Susan-Resiga D et al. J Biol Chem. 2017;292(5):1573-1590). In addition, this mutation has been reported as one of the most common amongst Czech, Polish, German, Austrian, and Slovak FH cohorts (Chmara M et al. J Appl Genet. 2010;51(1):95-106; Tichy et al. Atherosclerosis. 2012;223(2):401-8; Gabová D et al. Physiol Res. 2017;66(1):75-84). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;.;.;.;.;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

H;.;.;.;.;H

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-7.5

D;D;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

0.88

P;.;.;.;.;.

Vest4

0.96

MVP

1.0

MPC

0.87

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.99

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