Submissions for variant NM_000527.5(LDLR):c.2043C>A (p.Cys681Ter)

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000003887	SCV000264002	pathogenic	Hypercholesterolemia, familial, 1	2015-11-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000590806	SCV000285024	pathogenic	Familial hypercholesterolemia	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys681*) 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 (rs121908031, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1959928, 11668627, 19319977, 21145767, 22487947, 25461735). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys660*. ClinVar contains an entry for this variant (Variation ID: 3699). For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation	RCV000003887	SCV000295837	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000003887	SCV000484730	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	RCV000003887	SCV000503452	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 31 (1 homozygote) , family members = 17 with co-segregation / FH-Libanon, < 2% LDLR Activity
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000003887	SCV000540853	pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000481771	SCV000568525	pathogenic	not provided	2024-04-08	criteria provided, single submitter	clinical testing	Nonsense 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; Reported many times in the heterozygous, compound heterozygous, and homozygous states in individuals with FH (PMID: 9664576, 9259195, 3025214, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711); Considered a Lebanese founder mutation and may account for greater than 80% of FH cases in this population (PMID: 19319977); Published functional studies suggest a damaging effect on protein expression and binding (PMID: 31578082); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(C660X); This variant is associated with the following publications: (PMID: 31447099, 22487947, 25487149, 25525159, 3025214, 9259195, 9664576, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711, 29407885, 34040191, 33303402, 34037665, 32041611, 33740630, 32770674, 33418990, 32231684, 35379577, 32009526, 33955087, 34321884, 15321837, 19319977, 37128917, 31578082)
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003887	SCV000583922	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003887	SCV000588629	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000003887	SCV000607668	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590806	SCV000697220	pathogenic	Familial hypercholesterolemia	2016-10-26	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.2043C>A (p.Cys681X) 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. Truncations downstream of this position have been classified in the pathogenic spectrum by our laboratory (e.g. p.Trp813X, p.Ser710fsX2 ). Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121136 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). It was observed in several FH families and showed co-segregation with the disease indicating causality. Moreover, the variant was shown to result in lack of detectable high affinity binding and uptake of LDL, further supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844750	SCV000731826	pathogenic	Homozygous familial hypercholesterolemia	2021-02-22	criteria provided, single submitter	clinical testing	The p.Cys681X variant in LDLR has been reported in >80 individuals with hypercholesterolemia across several studies and segregated with disease in >10 affected relatives (Abifadel 2009, Banares 2017, Fahed 2011, Jannes 2015, Lehrman 1987, Tichy 2012, Vandrovcova 2013). This variant is considered to be a founder variant in the Lebanese population (Fahed 2016). This variant has also been reported in Clinvar (Variation ID 3699) and has been identified in 1/113666 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 681, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PVS1, PS4, PM2, PP1_Strong.
Iberoamerican FH Network	RCV000003887	SCV000748104	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Gharavi Laboratory, Columbia University	RCV000481771	SCV000809473	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000003887	SCV000894178	pathogenic	Hypercholesterolemia, familial, 1	2018-10-31	criteria provided, single submitter	clinical testing
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	RCV000003887	SCV000987033	pathogenic	Hypercholesterolemia, familial, 1	2018-08-09	criteria provided, single submitter	clinical testing	The nucleotide substitution c.2043C> A leads to a premature termination of protein synthesis at position 681 and is described as "FH Lebanese allele" in the literature. The mutation leads to intracellular degradation of the LDL receptor and loss of function. The mutation described here has also been described in patients with hypercholesterolemia and is therefore classified as pathogenic. PMID: 1453433, 3025214
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000003887	SCV000987528	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481771	SCV001134256	pathogenic	not provided	2023-03-06	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of LDLR protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251278 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as a Lebanese founder mutation, but has also been identified in multiple other ethnic groups, in individuals and families with familial hypercholesterolemia (PMID: 28873201 (2017), 25461735 (2015), 22487947 (2012), 21145767 (2011), 19319977 (2009), 14974088 (2004), 11668627 (2001), 9664576 (1998), 3025214 (1987)). In a functional study, this variant was found to have a damaging effect on LDLR expression and binding (PMID: 31578082 (2019)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000590806	SCV001352605	pathogenic	Familial hypercholesterolemia	2023-10-19	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 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.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000003887	SCV001432604	pathogenic	Hypercholesterolemia, familial, 1	2019-05-11	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000590806	SCV001435011	pathogenic	Familial hypercholesterolemia	2018-07-31	criteria provided, single submitter	clinical testing	The c.2043C>A (p.Cys681*) variant in the LDLR gene has been reported in multiple individual patients with familial Hypercholesterolemia and segregated in the families (PMID: 3025214, 1959928, 1453433, 12406975, 22487947). This variant is extremely rare in general population and is predicted to introduce a premature translation termination codon. Therefore, the c.2043C>A (p.Cys681*) variant in the LDLR gene is classified as pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV004584310	SCV002578008	pathogenic	See cases	2021-03-04	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PP1,PP5
Ambry Genetics	RCV002415394	SCV002719816	pathogenic	Cardiovascular phenotype	2022-08-29	criteria provided, single submitter	clinical testing	The c.2043C>A (p.C681*) alteration, located in exon 14 (coding exon 14) of the LDLR gene, consists of a C to A substitution at nucleotide position 2043. This changes the amino acid from a cysteine (C) to a stop codon at amino acid position 681. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration, also noted as p.C660X or the Lebanese allele, has been reported in individuals with familial hypercholesterolemia and a founder effect was proposed (Lehrman, 1987; Abifadel, 2009; Fahed, 2012). Based on the available evidence, this alteration is classified as pathogenic.
Revvity Omics, Revvity	RCV000003887	SCV003819453	pathogenic	Hypercholesterolemia, familial, 1	2022-11-14	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003887	SCV004175941	pathogenic	Hypercholesterolemia, familial, 1	2023-11-21	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM2_SUP,PP1
Mayo Clinic Laboratories, Mayo Clinic	RCV000481771	SCV004227682	pathogenic	not provided	2023-05-04	criteria provided, single submitter	clinical testing	PP1, PS3, PS4_moderate, PVS1
All of Us Research Program, National Institutes of Health	RCV000003887	SCV004818485	pathogenic	Hypercholesterolemia, familial, 1	2023-12-18	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 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 of Medical Genetics, National & Kapodistrian University of Athens	RCV000003887	SCV005091025	pathogenic	Hypercholesterolemia, familial, 1	2023-08-21	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5 - It's pathogenicity has already been established. ClinVar Variation ID 3699.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000481771	SCV005198662	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000003887	SCV005399191	pathogenic	Hypercholesterolemia, familial, 1	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia, 1 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants have been reported in heterozygous, compound heterozygous and homozygous state with the recessive disease being more severe (OMIM, PMID: 10978268). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic, and observed in individuals with familial hypercholesterolaemia (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both heterozygous and homozygous state in individuals with familial hypercholesterolaemia. It is regarded as a founder variant within the Lebanese population (ClinVar). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000003887	SCV000024052	pathogenic	Hypercholesterolemia, familial, 1	1991-11-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003887	SCV000268655	pathogenic	Hypercholesterolemia, familial, 1	2012-05-04	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003887	SCV000606582	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000590806	SCV002086860	pathogenic	Familial hypercholesterolemia	2020-08-17	no assertion criteria provided	clinical testing