19-11129534-T-TG

Position:

• chr19-11129534-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS4 PP1_Strong PVS1 PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2416dup (p.Val806fs) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PS4, PM2 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: PVS1 - variant is frameshift upstream of amino acid 830, so PVS1 is met.PP1_strong - variant segregates with the FH phenotype in- 1 informative meiosis from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 1 relative with the phenotype has the variant;- 7 informative meiosis from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): data from 4 families: 6 relatives with the phenotype have the variant plus 1 relative without the phenotype does not have the variant;8 informative meiosis support co-segregation, so PP1_Strong is met.PS4 - variant meets PM2 and was identified in - 6 unrelated index cases with DLCN>6 from Roberts Research Institute, Canada;- 1 index case with DLCN>6 from COLOR, USA;- 2 unrelated index cases who fulfill SB criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal;- 5 unrelated index cases who fulfill SB criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic;14 cases, so PS4 is metPM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PP4 - variant meets PM2 and was identified in 14 unrelated index cases from different labs (please see PS4 for details), so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA040715/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:25 U:1
• Conservation: PhyloP100: -1.43

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2416dup	p.Val806GlyfsTer11	frameshift_variant	17/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2416dup	p.Val806GlyfsTer11	frameshift_variant	17/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251326 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135886

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: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:14 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Feb 21, 2019	The mutation leads to the amino acid exchange valine to glycine at position 806 at protein level, as well as a premature termination of protein synthesis.The concomitant loss of LDL receptor activity has already been described in patients with hypercholesterolemia.This variant was observed in a patient with TC up to 360 mg/dl and LDL-C approx. 310 mg/dl. This mutation is therefore classified as pathogenic. PMID: 9767373, 10611908, 25846081 -
Pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/188 non-FH alleles -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	May 10, 2019	- -
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	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
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	Revvity Omics, Revvity	Jun 10, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). It is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 20217239). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000252330 / PMID: 9767373). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Aug 28, 2022	The NM_000527.5(LDLR):c.2416dup (p.Val806fs) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PS4, PM2 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: PVS1 - variant is frameshift upstream of amino acid 830, so PVS1 is met. PP1_strong - variant segregates with the FH phenotype in - 1 informative meiosis from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 1 relative with the phenotype has the variant; - 7 informative meiosis from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): data from 4 families: 6 relatives with the phenotype have the variant plus 1 relative without the phenotype does not have the variant; 8 informative meiosis support co-segregation, so PP1_Strong is met. PS4 - variant meets PM2 and was identified in - 6 unrelated index cases with DLCN>6 from Roberts Research Institute, Canada; - 1 index case with DLCN>6 from COLOR, USA; - 2 unrelated index cases who fulfill SB criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal; - 5 unrelated index cases who fulfill SB criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; 14 cases, so PS4 is met PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PP4 - variant meets PM2 and was identified in 14 unrelated index cases from different labs (please see PS4 for details), so PP4 is met. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 10, 2023	This variant inserts 1 nucleotide in exon 17 of the LDLR gene, creating a frameshift and 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. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 11754108, 22698793, 25461735, 28179607, 28235710, 29213121). This variant has been identified in 6/246154 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease in familial hypercholesterolemia. Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, 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 -
Pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -

Familial hypercholesterolemia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Val806Glyfs*11) 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 present in population databases (rs773618064, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 9767373, 10611908, 27816806). It has also been observed to segregate with disease in related individuals. This variant is also known as c.785insG, 2412-6insG and c.2416_2417insG (p.Val806Glyfs*10). ClinVar contains an entry for this variant (Variation ID: 252330). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Mar 01, 2019	The c.2416dupG (p.Val806Glyfs*11) variant in the LDLR gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple unrelated individuals affected with familial hypercholesterolemia (PMID 9767373, 10611908, 11754108, 12417285, 20217239) and has shown to segregate with disease in two families (PMID 10611908, 20217239). Therefore, this c.2416dupG (p.Val806Glyfs*11) variant in the LDLR gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 24, 2017	Variant summary: The LDLR c.2416dupG (p.Val806GlyfsX11) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 6/246402 control chromosomes (including gnomAD) at a frequency of 0.0000244, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The 6 occurrences observed in gnomAD need to be cautiously considered because the cohort could harbor individuals with an LDLR phenotype. Multiple publications have cited the variant in affected individuals including a large consanguineous Pakistani family that segregated across multiple generations, including one homozygous affected family member with a more severe phenotype (Ajmal_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 28, 2022	This variant inserts 1 nucleotide in exon 17 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 11754108, 22698793, 25461735, 28179607, 28235710, 29213121, 31345425). This variant has been identified in 6/246154 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease in familial hypercholesterolemia. Based on available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2022	Identified in multiple individuals from various ethnic backgrounds with a diagnosis of FH in the published literature (Ekstrm et al., 1998; Nobe et al., 1999; Fouchier et al., 2001; Liguori et al., 2001; Yu et al., 2002; Kuhrov et al., 2002; Miyake et al., 2009; Ajmal et al., 2010; Dukov et al., 2011; Bertolini et al., 2013; Jannes et al., 2015; Khera et al., 2016; Setia et al., 2016; Xiang et al., 2017; Fairoozy et al., 2017; Trinder et al., 2019); 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; Also known as c.785insG, c.2411insG, and c.2416_2417insG; This variant is associated with the following publications: (PMID: 23375686, 25846081, 11317362, 23535506, 11810272, 29213121, 25461735, 11754108, 10611908, 20217239, 18718593, 27050191, 21310417, 25682442, 28235710, 12417285, 27816806, 28994502, 31491741, 31345425, 32041611, 33303402, 32770674, 34037665, 33740630, 33418990, 33599434, 32331935, 9767373) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 16, 2019	This variant alters the translational reading frame of the LDLR mRNA and causes the premature termination of LDLR protein synthesis. This variant has been reported individuals with familial hypercholesterolemia (PMIDs: 27816806 (2016), 10611908 (1999), and 9767373 (1998)). Therefore, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 15, 2019

The p.Val806Glyfs11 variant in LDLR has been reported in more than 15 individuals with familial hypercholesterolemia (FH; over 10 heterozygotes, 3 homozygotes and 2 compound heterozygotes with other LDLR variants of uncertain significance) and segregated with disease in more than 13 affected relatives in at least 2 families (Ekstrom 1998, Nobe 1999, Fouchier 2001, Kuhrova 2002, Miyake 2009, Ajmal 2010, Tichy 2012, Setia 2016, Fairoozy 2017). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 252330) and has been identified in 0.01% (3/30614) of South Asian chromosomes and 0.002% (3/113724) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 806 and leads to a premature termination codon 11 amino acids downstream. Additionally, in vitro functional studies support an impact on protein function (Miyake 2009). Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PP1_Strong, PVS1, PS3_Supporting, PS4_Strong. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2022

The c.2416dupG pathogenic mutation, located in coding exon 17 of the LDLR gene, results from a duplication of G at nucleotide position 2416, causing a translational frameshift with a predicted alternate stop codon (p.V806Gfs*11). This alteration, historically identified as p.V785Gfs*11, has been reported in multiple individuals with familial hypercholesterolemia (FH) (Ekström U et al. Eur. J. Clin. Invest., 1998 Sep;28:740-7; Kuhrová V et al. Hum. Mutat., 2002 Jan;19:80; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Fan LL et al. Appl. Biochem. Biotechnol., 2015 May;176:101-9; Fairoozy RH et al. Sci Rep, 2017 Dec;7:17087). In addition, co-segregation with FH in a large Pakistani family has been reported (Ajmal M et al. Mol. Biol. Rep., 2010 Dec;37:3869-75). 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

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

Other links and lift over

dbSNP: rs773618064; hg19: chr19-11240210;