Submissions for variant NM_000527.5(LDLR):c.501C>A (p.Cys167Ter)

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211619	SCV000294744	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211619	SCV000484746	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	RCV000211619	SCV000503169	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 6 , family members = 4 with co-segregation
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000211619	SCV000540736	pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Invitae	RCV000589737	SCV000544686	pathogenic	Familial hypercholesterolemia	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys167*) 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: 7616128, 10208479, 12406975, 21382890, 22698793, 26892515, 27765764). This variant is also known as Cys146X. ClinVar contains an entry for this variant (Variation ID: 200918). For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211619	SCV000583687	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211619	SCV000588503	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589737	SCV000697234	pathogenic	Familial hypercholesterolemia	2016-12-20	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.501C>A (p.Cys167X) variant, alternatively also known as C146X, results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected truncate LDLR class A and B repeats, cysteine-rich domain, EGF-like calcium-binding domain, and EGF-like domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. p.Cys143X, p.Cys276X, p.Arg350X, etc.). This variant is absent in 121248 control chromosomes. In literature, this variant is reported as pathogenic variant and is found in many FH patients. The variant is particularly a frequent mutation in Dutch FH patients. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825616	SCV000966968	pathogenic	Homozygous familial hypercholesterolemia	2018-02-09	criteria provided, single submitter	clinical testing	The p.Cys167X variant in LDLR (also described as p.Cys146X in the literature) ha s been reported in the heterozygous state in >10 individuals with familial hyper cholesterolemia (FH), segregated with disease in one affected relative from one family (Lombardi 1995, Heath 1999, Fouchier 2001, Bodamer 2002, van der Graaf 20 11, Tichy 2012, Sharifi 2016) and was absent from large population studies. Addi tionally, this variant has been reported by other clinical laboratories in ClinV ar (Variation ID: 200918). This nonsense variant leads to a premature terminatio n codon at position 167, which is predicted to lead to a truncated or absent pro tein. Heterozygous loss of function of the LDLR gene is an established disease m echanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner bas ed upon predicted impact to the protein, presence in multiple affected individua ls and absence in the general population. ACMG/AMP Criteria applied (Richards 20 15): PVS1, PS4_Moderate, PM2.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211619	SCV001432607	pathogenic	Hypercholesterolemia, familial, 1	2019-05-11	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000589737	SCV001733673	pathogenic	Familial hypercholesterolemia	2020-07-13	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 15 individuals affected with familial hypercholesterolemia (PMID: 7616128, 10208479, 17539906, 21382890, 22698793, 23833242, 26892515, 27765764). This variant has not been identified 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.
Institute of Human Genetics, University Hospital Muenster	RCV002287383	SCV002577781	pathogenic	Hypercholesterolemia	2021-12-08	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PP3,PP5
Ambry Genetics	RCV002336450	SCV002644575	pathogenic	Cardiovascular phenotype	2021-12-06	criteria provided, single submitter	clinical testing	The p.C167* pathogenic mutation (also known as c.501C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 501. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This mutation (referred to as p.C146X) has been described in multiple unrelated individuals with familial hypercholesterolemia (Lombardi P et al. J. Lipid Res. 1995;36(4):860-7; Heath KE et al. Atherosclerosis 1999;143(1):41-54; Rieck L et al. Clin Genet. 2020 11;98(5):457-467). In in vitro functional studies, this variant showed significantly reduced or absent protein expression and function compared to wild type (Hu H et al. Lipids Health Dis. 2021 Sep;20(1):101). 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.
Fulgent Genetics, Fulgent Genetics	RCV000211619	SCV002775874	pathogenic	Hypercholesterolemia, familial, 1	2022-02-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000211619	SCV003827114	pathogenic	Hypercholesterolemia, familial, 1	2022-11-08	criteria provided, single submitter	clinical testing
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211619	SCV000268565	pathogenic	Hypercholesterolemia, familial, 1	2009-04-17	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211619	SCV000606136	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786348	SCV000925130	pathogenic	not provided		no assertion criteria provided	provider interpretation	Genetic testing: The patient had genetic testing for the familial LDLR mutation that was first identified in her brother, p.167*. at Ambry Genetics. Results reported on July 5, 2016 showed that the following variant was identified. Ambry classifies this variant as pathogenic. Given the loss of function nature of this variant and sufficient case data in other individuals we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant was previously identified in an affected family member of a patient. An individual with a missense variant at this codon is reported in Clinvar. Lombardi P et al. J. Lipid Res. 1995;36(4):860-7 reported this variant as it's other name (p.Cys146*) and Heath KE et al. Atherosclerosis 1999;143(1):41-54 reported this variant in a 27 Y male with FH. This variant is not reported in ExAC.
Natera, Inc.	RCV000589737	SCV001456143	pathogenic	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000786348	SCV001917128	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000786348	SCV001962793	pathogenic	not provided		no assertion criteria provided	clinical testing