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

Total submissions: 14

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	2017-08-08	criteria provided, single submitter	clinical testing	The E113X variant in the LDLR gene has been in multiple unrelated patients with FH (Hobbs et al., 1992; Wang et al., 2016; Bañares et al., 2017). This variant was also identified in a homozygous individual who was diagnosed with FH at nine months of age (Sanna et al., 2016). This E113X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014). Furthermore, the E113X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Iberoamerican FH Network	RCV000211560	SCV000748084	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	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
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