Submissions for variant NM_000527.5(LDLR):c.337G>T (p.Glu113Ter)

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211560	SCV000294637	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211560	SCV000484731	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	RCV000211560	SCV000503142	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 11 , family members = 8 with co-segregation
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211560	SCV000583663	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211560	SCV000588497	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
GeneDx	RCV000523979	SCV000617502	pathogenic	not provided	2024-01-05	criteria provided, single submitter	clinical testing	Has been reported in multiple unrelated individuals with FH (PMID: 28502510, 1301956, 27765764, 32041611, 33303402, 34037665, 34297352, 31345425, 11933210, 35052492, 11462246, 11196104); Not observed at significant frequency in large population cohorts (gnomAD); 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; Also known as E92X and FH Paris-5; This variant is associated with the following publications: (PMID: 25525159, 1301956, 32041611, 28502510, 33303402, 34297352, 33955087, 26894473, 27765764, 34037665, 31345425, 11933210, 35052492, 11462246, 11196104, 10532689, 10066037, 37128917)
Iberoamerican FH Network	RCV000211560	SCV000748084	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV002229195	SCV000833264	pathogenic	Familial hypercholesterolemia	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu113*) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 10532689, 11196104, 11462246, 11933210). This variant is also known as Stop 92, E92X. ClinVar contains an entry for this variant (Variation ID: 226320). For these reasons, this variant has been classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211560	SCV001432646	pathogenic	Hypercholesterolemia, familial, 1	2019-05-11	criteria provided, single submitter	research
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000211560	SCV001653587	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453756	SCV002614438	pathogenic	Cardiovascular phenotype	2022-05-11	criteria provided, single submitter	clinical testing	The p.E113* pathogenic mutation (also known as c.337G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 337. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. This alteration, also known as p.E92*, has been reported in patients with familial hypercholesterolemia (FH) (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Szalai C et al. Clin. Genet., 1999 Jan;55:67-8; Weiss N et al. J. Inherit. Metab. Dis., 2000 Dec;23:778-90; Salazar LA et al. Hum. Mutat., 2002 Apr;19:462-3). This alteration has also been reported in a homozygous state in a pediatric FH cohort (Sanna C et al. Atherosclerosis, 2016 Apr;247:97-104). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000211560	SCV002769519	pathogenic	Hypercholesterolemia, familial, 1	2021-05-06	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 hypercholesterolemia 1 and LDL cholesterol level QTL2 (MIM#143890). (I) 0107 - This gene is associated with autosomal dominant disease. (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 (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in many patients with familial hypercholesterolemia (ClinVar), both heterozygous (PMID:28502510) and homozygous (PMID:26894473). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000523979	SCV005198644	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211560	SCV000268558	pathogenic	Hypercholesterolemia, familial, 1	2013-05-28	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211560	SCV000606090	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research