Submissions for variant NM_000527.5(LDLR):c.2416dup (p.Val806fs)

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238458	SCV002568025	pathogenic	Hypercholesterolemia, familial, 1	2022-08-28	reviewed by expert panel	curation	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.
LDLR-LOVD, British Heart Foundation	RCV000238458	SCV000296001	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238458	SCV000323014	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/188 non-FH alleles
Robarts Research Institute, Western University	RCV000238458	SCV000484801	likely pathogenic	Hypercholesterolemia, familial, 1		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	RCV000238458	SCV000503487	uncertain significance	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 , family members = 2
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000238458	SCV000540871	pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000486216	SCV000568526	pathogenic	not provided	2022-04-30	criteria provided, single submitter	clinical testing	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)
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238458	SCV000583950	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000238458	SCV000588665	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000238458	SCV000607706	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000780378	SCV000823681	pathogenic	Familial hypercholesterolemia	2025-01-28	criteria provided, single submitter	clinical testing	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. 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780378	SCV000917581	pathogenic	Familial hypercholesterolemia	2017-10-24	criteria provided, single submitter	clinical testing	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.
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	RCV000238458	SCV000987034	pathogenic	Hypercholesterolemia, familial, 1	2019-02-21	criteria provided, single submitter	clinical testing	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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486216	SCV001134261	pathogenic	not provided	2019-02-16	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV000780378	SCV001352608	pathogenic	Familial hypercholesterolemia	2022-12-28	criteria provided, single submitter	clinical testing	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.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000238458	SCV001432638	pathogenic	Hypercholesterolemia, familial, 1	2019-05-10	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000780378	SCV001435013	pathogenic	Familial hypercholesterolemia	2019-03-01	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000238458	SCV002017122	pathogenic	Hypercholesterolemia, familial, 1	2022-06-10	criteria provided, single submitter	clinical testing
Arcensus	RCV000238458	SCV002564601	pathogenic	Hypercholesterolemia, familial, 1	2013-02-01	criteria provided, single submitter	clinical testing
3billion	RCV000238458	SCV002572924	pathogenic	Hypercholesterolemia, familial, 1	2022-09-01	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002450750	SCV002735991	pathogenic	Cardiovascular phenotype	2022-04-26	criteria provided, single submitter	clinical testing	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.
All of Us Research Program, National Institutes of Health	RCV000238458	SCV004820683	pathogenic	Hypercholesterolemia, familial, 1	2024-03-25	criteria provided, single submitter	clinical testing	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 20 unrelated heterozygous individuals affected with familial hypercholesterolemia (PMID: 11754108, 22698793, 25461735, 28179607, 28235710, 29213121, 31345425, 33599434, 34037665, 35741760; Color internal data). This variant has also been observed in homozygous state in three individuals affected with severe homozygous familial hypercholesterolemia (PMID: 33599434). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 35741760; ClinVar SCV002568025.1). This variant has been identified in 6/251326 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017567	SCV004847703	pathogenic	Homozygous familial hypercholesterolemia	2019-04-15	criteria provided, single submitter	clinical testing	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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000238458	SCV005874052	pathogenic	Hypercholesterolemia, familial, 1	2024-10-10	criteria provided, single submitter	clinical testing	PVS1, PM2, PP4, PP1_Strong
Clinical Genetics, Academic Medical Center	RCV000486216	SCV001926010	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000486216	SCV001963348	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000780378	SCV002086880	pathogenic	Familial hypercholesterolemia	2021-03-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745310	SCV005360020	pathogenic	LDLR-related disorder	2024-05-31	no assertion criteria provided	clinical testing	The LDLR c.2416dupG variant is predicted to result in a frameshift and premature protein termination (p.Val806Glyfs*11). This variant, also known as p.Val785Glyfs*11, has been reported in several patients with hypercholesterolemia (Kuhrová et al. 2002. PubMed ID: 11754108; Leren et al. 2021. PubMed ID: 33740630. Table S1). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in LDLR are expected to be pathogenic, and this variant has been interpreted as pathogenic by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (VCEP, https://www.ncbi.nlm.nih.gov/clinvar/variation/252330/). This variant is interpreted as pathogenic.