Submissions for variant NM_000527.4(LDLR):c.313+1G>A (rs112029328)

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000844753	SCV000271388	pathogenic	Familial hypercholesterolemia - homozygous	2015-12-23	criteria provided, single submitter	clinical testing	The c.313+1G>A variant in LDLR has been reported in >140 individuals with famili al hypercholesterolemia (FH) and segregated with disease in at least 5 affected relatives from 2 families (Leren 1994, Sun 1995, Lombardi 2000, Hooper 2012). Th is variant has also been identified in 7/111670 European chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs11202 9328). However, this frequency is low enough to be consistent with the frequency of FH in the general population. The c.313+1G>A variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause alt ered splicing leading to an abnormal or absent protein. Furthermore, in vitro fu nctional studies provide some evidence that this variant may impact protein func tion (Sun 1995, Cameron 2009). Heterozygous loss of LDLR function is an establis hed disease mechanism in familial hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant m anner based upon presence in multiple affected individuals, segregation studies, low frequency in the general population, functional evidence and the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PS4, PM2, PP1_Moderate, PS3_supporting.
LDLR-LOVD, British Heart Foundation	RCV000003934	SCV000294604	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000003934	SCV000322888	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research	0/208 non-FH alleles; 0/100 healthy control individuals
Robarts Research Institute,Western University	RCV000003934	SCV000484776	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	RCV000003934	SCV000503132	likely benign	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4/FH-Europe
Invitae	RCV000791438	SCV000544679	pathogenic	Familial hypercholesterolemia	2018-10-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the LDLR gene. It is has been shown to disrupt mRNA splicing and results in an absent or disrupted protein product (PMID: 19361455, 22390909). Truncating variants in LDLR are known to be pathogenic (PMID: 20809525). This particular variant has been shown to segregate with familial hypercholesterolemia (PMID: 7718019) and has been observed in multiple unrelated individuals with hypercholesterolemia (PMID: 22390909, 20045108, 10532689, 14974088) and early-onset myocardial infarction (PMID: 25487149). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000058917	SCV000583373	pathogenic	not provided	2019-01-09	criteria provided, single submitter	clinical testing	The c.313+1 G>A pathogenic variant in the LDLR gene has been previously reported in association with both heterozygous and homozygous FH (Leren et al., 1994; Lombardi et al., 1995; Jensen et al., 1999; Deiana et al., 2000; Lombardi et al., 2000; Dedoussis et al., 2004; Bourbon et al., 2008; Chmara et al., 2010; Romano et al., 2010; Hooper et al., 2012; Huijgen et al., 2012; Ma et al., 2017) as well as early-onset myocardial infarction (Do et al., 2015). This variant has also been described as a founder mutation in the Norwegian population (Leren et al., 1994). In addition, c.313+1 G>A has been identified in other individuals referred for FH genetic testing at GeneDx. Furthermore, the c.313+1 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.313+1 G>A variant destroys the canonical splice donor site in intron 3 and is predicted to cause abnormal gene splicing. Functional studies by Cameron et al. (1999) demonstrated that c.313+1G>A disrupts mRNA splicing, resulting in a transcript which skips exon 3 and includes intron 3, and producing a receptor with a reduced ability to internalize low density lipoprotein. Multiple other splice site variants in the LDLR gene, including two different pathogenic variants affecting the same nucleotide (c.313+1 G>T, c.313+1 G>C), have been reported in the Human Gene Mutation Database in association with hypercholesterolemia (Stenson et al., 2014).
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003934	SCV000583655	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003934	SCV000588493	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000003934	SCV000607443	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Athena Diagnostics Inc	RCV000058917	SCV000614008	pathogenic	not provided	2017-06-30	criteria provided, single submitter	clinical testing
Iberoamerican FH Network	RCV000003934	SCV000748082	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine	RCV000003934	SCV000839995	pathogenic	Familial hypercholesterolemia 1	2017-08-21	criteria provided, single submitter	clinical testing	The c.313+1G>A variant in LDLR gene destroys the canonical splice donor site in intron 3 and is predicted to result in abnormal splicing of the LDLR message. Functional studies have shown that the c.313+1G>A variant disrupts mRNA splicing and produces a protein with abnormal function (PMID 19361455). This variant has been reported in multiple unrelated individuals with hypercholesterolemia (PMID 7718019, 22390909, 22883975, 20045108, 20145306, 15523646) and individuals with early-onset myocardial infarction (PMID 25487149). This variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000058917	SCV000888166	pathogenic	not provided	2018-07-16	criteria provided, single submitter	clinical testing
OMIM	RCV000003934	SCV000024099	pathogenic	Familial hypercholesterolemia 1	1996-10-16	no assertion criteria provided	literature only
SNPedia	RCV000058917	SCV000090438	not provided	not provided		no assertion provided	not provided
Blueprint Genetics	RCV000003934	SCV000207022	pathogenic	Familial hypercholesterolemia 1	2014-09-25	no assertion criteria provided	clinical testing
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003934	SCV000268554	pathogenic	Familial hypercholesterolemia 1	2008-06-09	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000003934	SCV000606074	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen	RCV000003934	SCV000733814	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University	RCV000058917	SCV000924843	likely pathogenic	not provided	2017-02-09	no assertion criteria provided	provider interpretation	Genetic testing: The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results reported on October 17, 2017 showed that the following variant was identified (see report below): c.313+1G>A in the LDLR gene (NM_000527.4) Ambry classifies this variant as pathogenic. Given sufficient case data and functional in vitro studies, we consider this variant very likely disease causing and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant is a common cause of FH around the world. It is referred to as the FH-Elverum allele and the FH-Olbia allele. It's been identified in multiple populations around the world including Austria, Belgium, Denmark, Germany, Italy, Spain, Korea, Norway, The Netherlands, Russia, UK, Sweden, and South Africa (black). It's been identified in up to 25% of Norwegian FH patients and 5% of Western Australian patients. IT has also been reported in a case of homozygous FH. It has been written about in 14 publications and is listed as pathogenic or likely pathogenic by all seven entries in clinvar. An in vitro study found this mutation leads to several alternatively spliced transcripts, one of which skips exon 3 and can result in an abnormal LDLR protein with reduced function (Cameron et al. Clin Chim Acta. 2009. 403(1-2):13-15). This variant is located near a CpG enriched region which may be a mutational hot spot. This variant likely leads to loss of function of the LDL-receptor given its exon skipping nature. There are seven individuals with variation at c.313+1 position listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on 126,184 unrelated individuals at this position who are of African, Asian, European, Latino, and Ashkenazi descent. All 7 individuals are of European descent. This corresponds to about 1 in 8,015 European individuals in the general population which confirms that it's likely a common cause of FH in the European populations.