19-11105599-C-G

Position:

chr19-11105599-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM1PP3PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.693C>G (p.Cys231Trp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, PP4 and PS4_Supporting) 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: PM1 - Missense at codon 231. PM2 is Met and Cys231 is one of the 60 Cys residues listed, so PM1 is Met.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.708. It is not above 0.75, splicing evaluation is required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 5.84; canonical site wt = 7.67. Ratio variant/wt canonical: 5.84/7.67 = 0.761. --- ratio is below 0.8, so PP3 is Met.PP4 - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs.PS4_supporting - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585085/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LDLR
NM_000527.5 missense, splice_region

Scores

12

4

3

Splicing: ADA: 0.001641

2

Clinical Significance

Likely pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: -0.338

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 7 ACMG points.

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.

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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.693C>G	p.Cys231Trp	missense_variant, splice_region_variant	4/18	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.693C>G	p.Cys231Trp	missense_variant, splice_region_variant	4/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

2

AN:

149990

Hom.:

0

Cov.:

33

FAILED QC

Gnomad AFR

AF:

0.0000243

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000102

AC:

121

AN:

1190490

Hom.:

0

Cov.:

33

AF XY:

0.0000837

AC XY:

50

AN XY:

597088

show subpopulations

Gnomad4 AFR exome

AF:

0.0000357

Gnomad4 AMR exome

AF:

0.0000237

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000121

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.0000472

Gnomad4 NFE exome

AF:

0.000120

Gnomad4 OTH exome

AF:

0.0000612

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000133

AC:

2

AN:

150132

Hom.:

0

Cov.:

33

AF XY:

0.0000136

AC XY:

1

AN XY:

73418

show subpopulations

Gnomad4 AFR

AF:

0.0000243

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:

0.0000148

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:5

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 07, 2021	The NM_000527.5(LDLR):c.693C>G (p.Cys231Trp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, PP4 and PS4_Supporting) 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: PM1 - Missense at codon 231. PM2 is Met and Cys231 is one of the 60 Cys residues listed, so PM1 is Met. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.708. It is not above 0.75, splicing evaluation is required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 5.84; canonical site wt = 7.67. Ratio variant/wt canonical: 5.84/7.67 = 0.761. --- ratio is below 0.8, so PP3 is Met. PP4 - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs. PS4_supporting - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs. -
Likely pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 16, 2023	This variant has been reported in multiple individuals with familial hypercholesterolemia (PMID: 20809525, 24956927). It is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. This missense substitution occurs at an amino acid position that is known to be critical to protein structure/function. Other missense substitutions at this amino acid residue have been previously reported in individual(s) with disease and classified as pathogenic, which supports the functional importance of this position (PMID: 19073363, 27830735, 10422804, 11313767, 22698793). -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
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	subject mutated among 2600 FH index cases screened = 1 , family member = 1 / Software predictions: Damaging -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2017

The p.C231W pathogenic mutation (also known as c.693C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 693. The cysteine at codon 231 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration, also referred to as C210W, has been reported in association with hypercholesterolemia (Marduel M et al. Hum Mutat. 2010;31:E1811-24; Norsworthy PJ et al. BMC Med Genet. 2014;15:70). In addition, multiple alterations at the same amino acid position have also been detected in individuals with familial hypercholesterolemia, including C231G (Sundvold H et al. Hum Mutat. 1996;7:70-1), C231R (Wang L et al. Nutr Metab Cardiovasc Dis. 2009;19:391-400) and C231Y (Shin JA et al. Clin Genet. 2000;57:225-9). 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

0.99

BayesDel_addAF

Pathogenic

0.49

D

BayesDel_noAF

Pathogenic

0.46

CADD

Benign

18

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.98

D;.;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.58

FATHMM_MKL

Uncertain

0.81

D

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.75

D

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.94

D

MutationAssessor

Pathogenic

4.8

H;.;.;H

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.62

T

PROVEAN

Pathogenic

-9.8

D;D;D;D

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.94

MutPred

0.76

Gain of catalytic residue at C231 (P = 0.009);Gain of catalytic residue at C231 (P = 0.009);.;Gain of catalytic residue at C231 (P = 0.009);

MVP

1.0

MPC

0.95

ClinPred

1.0

D

GERP RS

-2.4

Varity_R

0.99

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.24

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.

Other links and lift over

dbSNP: rs121908035; hg19: chr19-11216275;