19-11100236-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM1PS3_ModeratePP3PP4PP1PS4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.81C>G (p.Cys27Trp) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PS3_moderate, PS4, PP1, PP3 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:PM1: Variant meets PM2 and alters Cys27, one of the cysteine residues listed.PM2: PopMax MAF = 0.00003518 (0.004%) in European (non-Finnish) exomes (gnomAD v2.1.1).PS3_moderate: PMID:1301956 - Level 2 assay- study on hmz patient's fibroblast cell, LDLR activity value range: 15-30%.PS4: Variant meets PM2. Variant identified in >15 index cases - 1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome possible- 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch lipid clinic network >=6- 2 cases from Robarts Research Institute with Dutch lipid clinic network >=6- 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca with Dutch lipid clinic network >=6-as well as >10 cases from (PMID:1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425) PP1: Variant segregates with FH phenotype in at least 2 informative meiosis (minimum 2) from 2 families from different labs (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, and Laboratory of Genetics and Molecular Cardiology)PP3: REVEL = 0.759PP4: Variant meets PM2 and is identified in several index case who fulfil SB/DLCN>6/MedPed/other criteria for FH from different labs (see PS4), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA041664/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 1 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:31B:1

Conservation

PhyloP100: -0.152

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 13 ACMG points.

PS3

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

PS4

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

PM1

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.

PP3

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 link	c.81C>G	p.Cys27Trp	missense_variant	Exon 2 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.81C>G	p.Cys27Trp	missense_variant	Exon 2 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151930

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250746

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135548

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1460888

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726738

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151930

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74178

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000296

Hom.:

2197

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:21Benign:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 24, 2021

Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2012

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

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

- -

Jun 14, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Robarts Research Institute, Western University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging -

Sep 16, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with tryptophan at codon 27 in the LDLR type A repeat 1 of the LDLR protein. This variant is also known as p.Cys6Trp in the mature protein, and as FH San Francisco in the literature. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study using cells derived from a homozygous carrier individual has shown that this variant causes the mutant protein to retain 15-30% of receptor activity compared with the wild type LDLR protein (PMID: 1301956). This variant has been reported in over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425, 33807407, 34297352, 37370883). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in three individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 19026292, 23375686). This variant has been identified in 4/250746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.79_81delinsCGT (p.Cys27Arg), is considered to be disease-causing (ClinVar variation ID: 921285), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Aug 26, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PM2,PP3 -

Jan 21, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 13, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PM5, PP3, PP5- This variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 226304). Low frequency in gnomAD population databases. -

Oct 27, 2021

Institute of Human Genetics, Heidelberg University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2021

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 24, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

ACMG Guidelines: Pathogenic (ii) -

Aug 06, 2018

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The mutation at the protein level at position 27 (position 6 of the mature protein) leads to the amino acid change of cysteine to tryptophan (p.Cys27Trp, old nomenclature: p.Cys6Trp). This change has already been described in the literature as a San Francisco allele and is associated with elevated cholesterol and LDL-C levels. Impairment of LDL receptor activity has been demonstrated. We observed a patient with that kind of mutation with average values of TC = 330 and LDL-C of 280 mg/dl. PMID: 1301956, 23375686, 27497240 -

Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disrupt disulfide bridge between Cys27 and Cys39. -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Cys27Trp variant in LDLR has been reported in 54 individuals (including 47 Greek individuals) with Familial Hypercholesterolemia (PMID: 11317361, 11668627, 9259195, 1301956, 25463123, 19026292), segregated with disease in 37 affected relatives from 18 families, and has been identified in 0.003518% (4/113686) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2228671). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic, likely pathogenic, and likely benign in ClinVar (Variation ID: 226304). In vitro functional studies provide some evidence that the p.Cys27Trp variant may slightly impact protein function (PMID: 1301956). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on cosegregation with Familial Hypercholesterolemia and greater prevalence in individuals with Familial Hypercholesterolemia than in control cohorts. ACMG/AMP Criteria applied: PS4, PP1_Strong, PP3, PS3_supporting (Richards 2015). -

May 06, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000527.5(LDLR):c.81C>G (p.Cys27Trp) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PS3_moderate, PS4, PP1, PP3 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: PM1: Variant meets PM2 and alters Cys27, one of the cysteine residues listed. PM2: PopMax MAF = 0.00003518 (0.004%) in European (non-Finnish) exomes (gnomAD v2.1.1). PS3_moderate: PMID:1301956 - Level 2 assay - study on hmz patient's fibroblast cell, LDLR activity value range: 15-30%. PS4: Variant meets PM2. Variant identified in >15 index cases - 1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome possible - 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch lipid clinic network >=6 - 2 cases from Robarts Research Institute with Dutch lipid clinic network >=6 - 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca with Dutch lipid clinic network >=6 -as well as >10 cases from (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425) PP1: Variant segregates with FH phenotype in at least 2 informative meiosis (minimum 2) from 2 families from different labs (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, and Laboratory of Genetics and Molecular Cardiology) PP3: REVEL = 0.759 PP4: Variant meets PM2 and is identified in several index case who fulfil SB/DLCN>6/MedPed/other criteria for FH from different labs (see PS4), after alternative causes of high cholesterol were excluded. -

not provided

Pathogenic:4

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PM1, PM2, PP4:Moderate, PS4:Moderate, PP3, PS3:Supporting -

Jun 30, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Jan 09, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also known as p.(C6W) or FH San Francisco; 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; Participates in disulfide bonding with another cysteine residue which is critical for correct protein structure, and is located in the LDL-receptor class A1 repeat domain which is necessary for ligand binding (Sudhof et al., 1985; Rudenko et al., 2002); Reported in ClinVar (ClinVar Variant ID# 226304; ClinVar); This variant is associated with the following publications: (PMID: 17539906, 19062533, 11317361, 11668627, 9259195, 27497240, 16250003, 25463123, 19026292, 14974088, 21925044, 27578104, 27765764, 27824480, 22883975, 17426749, 22836074, 24075752, 21310417, 1301956, 29284604, 19060911, 31447099, 32977124, 32041611, 32719484, 33740630, 34037665, 2988123, 12459547, 23375686) -

Familial hypercholesterolemia

Pathogenic:4

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 27 of the LDLR protein (p.Cys27Trp). This variant is present in population databases (rs2228671, gnomAD 0.004%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11668627, 14974088, 19026292, 25463123, 27497240, 27824480). 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 C6W. ClinVar contains an entry for this variant (Variation ID: 226304). 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 affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic. -

Jan 12, 2017

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 LDLR c.81C>G (p.Cys27Trp) variant (alternatively also known as C6W and FH San Francisco) substitutes a Cys residue located in LDL receptor class A repeat which forms ligand binding domain (InterPro, Klancar_2015, Bertolini_2013, Hobbs_1992). The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation (InterPro, PMID: 6091915). Therefore, this variant is predicted to be deleterious for protein function as it breaks down one of the disulphide bonds. 5/5 in silico tools also predict damaging outcome for this variant. This variant was found in 2/121358 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). In literature, this variant is widely reported as a pathogenic variant found mainly in FH patients of European origin (Klancar_2015, Mollaki_2014,Kolansky_2008, Bertolini_2013, Day_1997, Hobbs_1992). Genotype-phenotype correlation study showed that this variant causes a milder disease (Mollaki_2014). A functional study showed that this variant leads to impaired LDL receptor activity (Hobbs_1992). Multiple reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as Pathogenic. -

Oct 02, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.81C>G (p.Cys27Trp) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 16250003, 23375686) and is extremely rare in the general population. Functional studies have reported that the mutant LDLR protein retains 15-30% of receptor activity compared with wildtype LDLR protein (PMID: 1301956). Therefore, this c.81C>G (p.Cys27Trp) variant in the LDLR gene is classified as likely pathogenic. -

Mar 29, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Cys6Trp in the mature protein) replaces cysteine with tryptophan at codon 27 in the LDLR type A repeat 1 of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). 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 performed with cells from an individual affected with homozygous familial hypercholesterolemia has indicated that the mutant protein retains 15-30% of receptor activity compared with the wild type LDLR protein (PMID: 1301956). This variant has been observed in over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425, 33807407, 34297352). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia, indicating that this variant contributes to disease (PMID: 19026292, 23375686). This variant has been identified in 4/250746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

See cases

Pathogenic:1

Dec 05, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PM1,PM2,PP2,PP4,PP5,BP1 -

Cardiovascular phenotype

Pathogenic:1

Sep 29, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C27W pathogenic mutation (also known as c.81C>G), located in coding exon 2 of the LDLR gene, results from a C to G substitution at nucleotide position 81. The cysteine at codon 27 is replaced by tryptophan, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration has been reported in numerous familial hypercholesterolemia cohorts (e.g., Miltiadous G et al. Hum. Mutat. 2001;17:432-3; Dedoussis GV et al. Eur. J. Clin. Invest. 2004;34:402-9; Kolansky DM et al. Am. J. Cardiol. 2008;102:1438-43; Mollaki V et al. Atherosclerosis. 2014;237:798-804). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 1 (Ambry internal data). Two functional studies have indicated that this alteration leads to reduced LDLR activity, but data were not provided (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Dedoussis GV et al. Eur. J. Clin. Invest. 2004;34:402-9). 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

0.96

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.47

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;.;.;.;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.82

T;T;T;T;T;T

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.9

H;.;H;H;H;H

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-9.2

D;D;D;D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.91

MutPred

0.83

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

1.0

MPC

0.95

ClinPred

1.0

GERP RS

-1.7

Varity_R

0.98

gMVP

1.0

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