chr19-11105599-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000527.5(LDLR):c.693C>A(p.Cys231*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000298 in 1,344,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C231C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000025 ( 0 hom. )

Consequence

LDLR
NM_000527.5 stop_gained, splice_region

Scores

Splicing: ADA: 0.00009398

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: -0.338

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 1
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-11105599-C-A is Pathogenic according to our data. Variant chr19-11105599-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.693C>A	p.Cys231*	stop_gained, splice_region_variant	Exon 4 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.693C>A	p.Cys231*	stop_gained, splice_region_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000667

AC:

AN:

150004

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000251

AC:

AN:

1194078

Hom.:

Cov.:

AF XY:

0.00000334

AC XY:

AN XY:

598810

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28076

American (AMR)

AF:

0.00

AC:

AN:

42224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22420

East Asian (EAS)

AF:

0.00

AC:

AN:

32986

South Asian (SAS)

AF:

0.00

AC:

AN:

81182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3962

European-Non Finnish (NFE)

AF:

0.00000336

AC:

AN:

891660

Other (OTH)

AF:

0.00

AC:

AN:

49164

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.022510), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000667

AC:

AN:

150004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41090

American (AMR)

AF:

0.00

AC:

AN:

15078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

4904

South Asian (SAS)

AF:

0.00

AC:

AN:

4592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67544

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000272

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:9

Jul 09, 2008

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 21, 2023

deCODE genetics, Amgen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

The variant NM_000527.5:c.693C>A (chr19:11105599) in LDLR was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). Following imputation in a set of 166K Icelanders (4 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 3.59, P= 4.14e-10) and Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 3.26, P= 1.50e-08). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PVS1, PS4, PM2 ) this variant classifies as pathogenic. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

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:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

subjects mutated among 2600 FH index cases screened = 4 , family members = 9 with co-segregation -

Robarts Research Institute, Western University

Significance:Likely 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: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

- -

Familial hypercholesterolemia

Pathogenic:3

Jun 18, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pathogenic variant based on current evidence: This variant is a single nucleotide substitution in exon 4 of the LDLR gene, which creates a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 8093663, 16389549, 22883975). Truncating variants in LDLR are known to be pathogenic (PMID: 20809525). Based on available evidence, this variant is classified as Pathogenic. -

Sep 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Cys231*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 8093663, 10559517, 16389549, 20145306, 21310417, 22698793, 22883975, 27680772). This variant is also known as Cys210X. ClinVar contains an entry for this variant (Variation ID: 3730). For these reasons, this variant has been classified as Pathogenic. -

Jul 30, 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.693C>A (p.Cys231X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 244710 control chromosomes. c.693C>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Martin_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27680772). ClinVar contains an entry for this variant (Variation ID: 3730). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Sep 08, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.C231* pathogenic mutation (also known as c.693C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 693. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This alteration (also described as p.C210*) has been reported in familial hypercholesterolemia cohorts (Gudnason V et al. Arterioscler. Thromb., 1993 Jan;13:56-63; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Du&scaron;ková L et al. Atherosclerosis, 2011 May;216:139-45). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.71

FATHMM_MKL

Uncertain

0.80

PhyloP100

-0.34

Vest4

0.85

GERP RS

-2.4

PromoterAI

-0.0072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000094

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

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chr19-11105599-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over