Variant chr19-11113651-ACT-A details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 19-11113651-ACT-A is Pathogenic according to our data. Variant chr19-11113651-ACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113651-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1478_1479del	p.Ser493CysfsTer42	frameshift_variant	10/18	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.1478_1479del	p.Ser493CysfsTer42	frameshift_variant	10/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151968

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Cov.:

show subpopulations

Gnomad AFR

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0.00

Gnomad AMI

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0.00

Gnomad AMR

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0.00

Gnomad ASJ

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0.00

Gnomad EAS

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0.00

Gnomad SAS

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0.00

Gnomad FIN

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0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461810

Hom.:

AF XY:

0.00000275

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

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0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

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0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151968

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

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0.00

Gnomad4 ASJ

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0.00

Gnomad4 EAS

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0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:9

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- and EBV-transformed B-lymphocytes (with Ser123Pro). -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 14, 2023	The c.1478_1479del (p.Ser493Cysfs42) variant in the LDLR gene introduces a premature translation termination codon resulting in an absent or disrupted protein product. The variant has been reported in several individuals (>10) with familial hypercholesterolemia (FH) (PMID:7866407, 8740919, 11810272, 23833242, 28161202, 20145306, 33269076, 33794673, 19446849). This variant has also been reported in compound heterozygous status (with p.Ser123Pro) in an individual with FH, and in-vitro functional studies using patient-derived EBV transformed cell lines showed residual LDLR activity of about 32% compared to the normal controls (PMID: 20045108). This variant has been observed in homozygous status in an individual with severe FH (LDL-C: 17.6mmol/dL) (PMID: 29502162). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID:11810272) and by several ClinVar submitters (ClinVar ID: 222689, 432366). This variant is found to be rare (1/31342; 0.00003191) in the general population database (gnomAD) and interpreted as pathogenic by multiple submitters in the ClinVar (ClinVar ID: 222688). Therefore, the c.1478_1479del (p.Ser493Cysfs42) variant in the LDLR gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
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	subjects mutated among 2600 FH index cases screened = 4 , family members = 2 with co-segregation -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Mar 27, 2017	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Familial hypercholesterolemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 07, 2018	Variant summary: LDLR c.1478_1479delCT (p.Ser493CysfsX42) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1686G>A, p.Trp562X; c.2043C>A, p.Cys681X; c.2061dupC, p.Asn688fsX29). The variant allele was found at a frequency of 3.2e-05 in 30908 control chromosomes (gnomAD). The variant, c.1478_1479delCT, has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Cavanaugh_1994, Jensen_1996, Fouchier_2001, Romano_2011, Kusters_2013). 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, showing a 10%-30% of normal LDL uptake activity associated with this variant (Romano_2011). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2023	This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Ser493Cysfs*42) 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 premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7866407, 11810272, 20045108, 20145306, 21865347). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 222688). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 26, 2021	- -

LDLR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2024

The LDLR c.1478_1479delCT variant is predicted to result in a frameshift and premature protein termination (p.Ser493Cysfs*42). This variant has been well-documented to be pathogenic for Hypercholesterolemia (Chmara et al. 2010. PubMed ID: 20145306; Bertolini et al. 2020. PubMed ID: 32977124. Table S2; Sturm et al. 2021. PubMed ID: 34037665. eTable 1). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 19, 2024

Identified in multiple patients with FH in published literature (PMID: 7866407, 20145306, 28161202); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25911074, 8740919, 21865347, 7866407, 20145306, 7489239, 9974426, 11810272, 30586733, 29866529, 34040191, 32977124, 33269076, 33740630, 34037665, 34297352, 33955087, 30710474, 28161202) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2022

The c.1478_1479delCT pathogenic mutation, located in coding exon 10 of the LDLR gene, results from a deletion of two nucleotides at nucleotide positions 1478 to 1479, causing a translational frameshift with a predicted alternate stop codon (p.S493Cfs*42). This mutation has been previously reported in association with familial hypercholesterolemia (Cavanaugh JA et al. Hum. Mutat., 1994;4:276-80; Schuster H et al. Arterioscler. Thromb. Vasc. Biol., 1995 Dec;15:2176-80; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Romano M et al. J. Lipid Res., 2011 Nov;52:2095-100; Minicocci I et al. J. Pediatr., 2017 04;183:100-107.e3; Klaus G et al. Pediatr. Nephrol., 2018 Jul;33:1199-1208). 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

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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.

chr19-11113651-ACT-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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