Submissions for variant NM_000527.5(LDLR):c.682G>T (p.Glu228Ter) (rs121908029)

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211631	SCV000294907	pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute,Western University	RCV000211631	SCV000484711	likely pathogenic	Familial hypercholesterolemia 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	RCV000211631	SCV000503219	pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 7 , family member = 1 with co-segregation / FH-Morocco, 2% LDLR Activity
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211631	SCV000583726	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211631	SCV000599343	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	curation
Athena Diagnostics Inc	RCV000518828	SCV000614010	pathogenic	not provided	2013-06-27	criteria provided, single submitter	clinical testing
Invitae	RCV000589867	SCV000627046	pathogenic	Familial hypercholesterolemia	2019-11-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu228*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121908029, ExAC 0.01%). This variant has been reported in multiple unrelated individuals and affected with familial hypercholesterolemia (PMID: 1301956, 11462246, 15359125, 19843101, 21310417, 23054246). This variant is also known as p.Glu207* in the literature. ClinVar contains an entry for this variant (Variation ID: 226333). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000518828	SCV000680545	pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing	E228X (referred to as Stop207 and FH Morocco) has been reported previously as a novel variant in one individual of Moroccan American ancestry with primary hypercholesterolemia who was homozygous for E228X (Hobbs et al., 1992). E228X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Furthermore, this particular area of the LDLR gene appears to be a mutation hotspot, and 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 E228X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; Exome Variant Server).In summary, E228X in the LDLR gene is interpreted as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America	RCV000589867	SCV000697248	pathogenic	Familial hypercholesterolemia	2016-11-21	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.682G>T (p.Glu228X) variant (alternatively also known as E207X) 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. Functional analyses show that this variant results into NMD causing absent LDLR protein (Charng_2006) and/or extremely low LDL receptor activity (Hobbs_1992). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Cys276X, p.Val295fsX75). This variant is widely reported in FH patients and is a recurrent pathogenic mutation (Hobbs_1992, Leren_2004, Muller_2004, Charng_2006, Humphries_2006). This variant was found in 2/117006 control chromosomes at a frequency of 0.0000171, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). The heterozygotes in ExAC are likely to represent as subclinical cases or reduced penetrance. Multiple clinical lab/research centers have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000211631	SCV000894171	pathogenic	Familial hypercholesterolemia 1	2018-10-31	criteria provided, single submitter	clinical testing
Color	RCV000589867	SCV000903587	pathogenic	Familial hypercholesterolemia	2020-03-05	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000825617	SCV000966969	pathogenic	Homozygous familial hypercholesterolemia	2019-03-03	criteria provided, single submitter	clinical testing	The p.Glu228X variant in LDLR (also described as p.Glu207X in the literature) has been reported in 23 individuals with familial hypercholesterolemia (FH; Hobbs 1992, Nauck 2001, Bodamer 2002, Kim 2004, Taylor 2007, Hola 2009, Vandrovcova 2013, Han 2015, Du 2016, Abul-Husn 2016) and segregated with disease in 6 affected relatives from 3 families (Bodamer 2002, Kim 2004). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 226333). In vitro functional studies provide some evidence that the p.Glu228X variant may impact protein function (Hobbs 1992, Holla 2009). This variant has also been identified in 1/23818 African and 2/125438 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12190829). This frequency is low enough to be consistent with the frequency of FH in the general population. This nonsense variant leads to a premature termination codon at position 228, 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 individuals with FH. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, low frequency in the general population, predicted impact on the protein, and functional evidence. The ACMG/AMP criteria applied (Richards 2015): PVS1; PM2; PS4; PP1_Moderate; PS3_Supporting.
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen	RCV000211631	SCV000987035	pathogenic	Familial hypercholesterolemia 1	2018-10-09	criteria provided, single submitter	clinical testing	The mutation leads to a premature stop codon at protein level at position 228 (position 207 of the mature protein). This change has already been described in the literature as FH Morocco allele and is associated with elevated cholesterol and LDL-C levels. PMID: 1131376, 7649546, 7903864
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000211631	SCV000993423	pathogenic	Familial hypercholesterolemia 1	2019-03-20	criteria provided, single submitter	research	ACMG codes: PVS1, PS3, PS4, PP5
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000211631	SCV001432573	pathogenic	Familial hypercholesterolemia 1	2019-05-23	criteria provided, single submitter	research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211631	SCV000268582	pathogenic	Familial hypercholesterolemia 1	2011-08-11	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211631	SCV000606203	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000518828	SCV000925136	pathogenic	not provided	2017-11-16	no assertion criteria provided	provider interpretation	p.Glu228* (c.682G>T) in exon 4 of the LDLR gene (NM_000527.4; chr19-11216264-G-T) SCICD Classification: pathogenic variant based on strong case data. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: LDLR: LDL receptors are located on the surface of the liver and play an important role in LDL recycling. Pathogenic variants in LDLR account for 80% of cases of familial hypercholesterolemia. Both missense and truncating/frameshift variants can be pathogenic. Truncating variants in LDLR are a known mechanism of disease (Marduel et al 2010). Exon 4 in LDLR encodes a binding domain for both apoB and apoE. Case data (not including our patient): at least 12. ClinVar: LDLR-LOVD, British Heart Foundation, University of Western Ontario, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix (7 unrelated cases and segregated with disease in 1 family member), Lille University, Cardiovascular Research Group, Istituto Nacional de Saude Doutor Ricardo Jorge, Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital - all likely pathogenic or pathogenic. Cases in the literature: At least 12. Note: this variant is also known as p.Glu207* in the literature. Hobbs et al 1992: this variant caused less than 2% LDLR activity. The patient was Moroccan American. Nauck et al 2001: This variant was found in 5 patients with FH. Kim et al 2004: Found in 2 of 25 unrelated Korean patients with FH. Taylor et al 2010: Detected this variant in 1 of 20 patients with definite FH. Dušková et al 2011: detected in 1 of 1945 unrelated Czech patients with FH. Futema et al 2012: 2 of 48 patients with FH (British descent). Segregation data: none reported Functional data: Truncating variants in LDLR are a known mechanism of disease (Marduel et al 2010). Exon 4 in LDLR encodes a binding domain for both apoB and apoE (Hobbs et al 1992). Conservation data: The glutamic acid at codon 228 is completely conserved across species. Amino acid at position 227 is also completely conserved. Nearby pathogenic variants at this codon or neighboring codons: Many nearby truncating variants near this codon. Population data: Highest MAF in African population: 0.0066%. The variant was reported online in 2 of 122,195 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 7,543 individuals of African descent (MAF=0.0066%) and 1 of 55,223 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).