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

Total submissions: 38

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000003934	SCV001960918	pathogenic	Hypercholesterolemia, familial, 1	2021-06-07	reviewed by expert panel	curation	The NM_000527.4(LDLR):c.313+1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1_Strong, PS4, PP1_Strong, PM2, PS3_Moderate and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1_strong - Variant is in canonical GT +1 splice site, predicted to lead to exon 3 skipping (in frame). PS4 - Variant meets PM2. Identified in at least 14 unrelated index cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCS equal or above 6. PP1_strong - variant segregates with FH phenotype in 6 informative meiosis in 5 families from different laboratories. PM2 - PopMax MAF = 0.00006156 (0.006%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate Level 2 assays: PMID 19361455: Hmz patients' Epstein-Barr tranformed lymphocytes, RNA and FACS assays - results - Alternative splicing: skipping of exon 3 or inclusion of intron 3; amount of cell-surface LDLR 33% of normal (Hmz); 12% LDL-LDLR uptake in Hmz ---- Aberrant transcripts confirmed by sequencing and above 25% of total transcript, and uptake is below 70% of wild-type, so PS3_moderate is Met. PP4 - Variant meets PM2. Identified in 3 FH cases from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge who fulfill Simon-Broome criteria and in 13 FH cases from University of British Columbia (UBC, Canada) and 14 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with clinical Dutch Lipid Clinic Network Criteria score ≥ 6.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844753	SCV000271388	pathogenic	Homozygous familial hypercholesterolemia	2019-03-26	criteria provided, single submitter	clinical testing	The c.313+1G>A variant in LDLR has been reported in >140 individuals with familial hypercholesterolemia (FH) and segregated with disease in at least 5 affected relatives from 2 families (Leren 1994, Sun 1995, Lombardi 2000, Hooper 2012). This variant has also been identified in 7/111670 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). 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 altered splicing that would preserve the protein reading frame, leading to an abnormal protein. Furthermore, in vitro functional studies provide some evidence that this variant may impact protein function (Sun 1995, Cameron 2009). 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, and impact to the protein. The ACMG/AMP Criteria applied: PS4, PM2, PP1_Moderate, PVS1_Moderate.
LDLR-LOVD, British Heart Foundation	RCV000003934	SCV000294604	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000003934	SCV000322888	pathogenic	Hypercholesterolemia, familial, 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	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	RCV000003934	SCV000503132	likely benign	Hypercholesterolemia, familial, 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	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs112029328, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 10532689, 15701167, 19361455). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3736). Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 19361455). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000058917	SCV000583373	pathogenic	not provided	2022-06-23	criteria provided, single submitter	clinical testing	Described as a founder mutation in the Norwegian population (Leren et al., 1994); Published functional studies demonstrate that c.313+1 G>A leads to the production of two abnormal transcripts which impair LDL receptor function (Cameron et al., 1999); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#3736; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD; other references); This variant is associated with the following publications: (PMID: 25525159, 25487149, 10735632, 22883975, 30592178, 30795984, 31048103, 22390909, 10634824, 17765246, 7616128, 20145306, 20045108, 10532689, 14974088, 7718019, 25468658, 29233637, 31447099, 8911609, 32041611, 33303402, 32719484, 33226606, 33740630, 34037665, 19361455)
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003934	SCV000583655	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003934	SCV000588493	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000003934	SCV000607443	pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000003934	SCV000839995	pathogenic	Hypercholesterolemia, familial, 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	2023-02-03	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and interferes with normal LDLR mRNA splicing (PMID: 19361455 (2009)). The frequency of this variant in the general population, 0.000062 (7/113710 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals with familial hypercholesterolemia (FH) (PMID: 25487149 (2015), 22390909 (2012), 20045108 (2010), 14974088 (2004), 7616128 (1995)), and has been shown to segregate with disease (PMID: 8829662 (1996)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000791438	SCV001346458	pathogenic	Familial hypercholesterolemia	2023-08-07	criteria provided, single submitter	clinical testing	This variant (also known as FH-Elverum) causes a G to A nucleotide substitution at the +1 position of intron 3 of the LDLR gene, and is predicted to abolish the intron 3 canonical splice donor site. An experimental study has shown that this variant causes skipping of exon 3 and inclusion of intron 3, and no functional LDLR protein was produced from the mutant transcript (PMID: 19361455). The variant has been reported in over 500 individuals affected with familial hypercholesterolemia (PMID: 7616128, 7718019, 10532689, 14974088, 15241806, 16159606, 17539906, 17765246, 20045108, 20145306, 22883975, 28502510, 29233637, 29353225, 30795984, 33740630, 34037665) and is considered to be a founder mutation in the Norwegian population (PMID: 7718019, 33740630). In addition, a large case-control study has shown that this variant is associated with early-onset myocardial infarction (PMID: 25487149). This variant has been identified in 7/251424 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000791438	SCV001372436	pathogenic	Familial hypercholesterolemia	2020-06-16	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.313+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions indicating that this variant results in two mutant transcripts, one has skipping of exon 3 and the other has inclusion of intron 3 (Cameron_2009, Jensen_1996). The transcript with skipping of exon 3 was demonstrated to have considerably reduced cell-surface LDLR and total amounts of internalized LDL, indicating that the variant LDLR is markedly dysfunctional (Cameron_2009). The variant allele was found at a frequency of 2.8e-05 in 251424 control chromosomes (gnomAD). c.313+1G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Deiana_2000, Jensen_1996, Mozas_2004, Leren_1994). These data indicate that the variant is very likely to be associated with disease. Fourteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (n=13) and as likely benign (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003934	SCV001429402	pathogenic	Hypercholesterolemia, familial, 1	2021-01-21	criteria provided, single submitter	clinical testing
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000003934	SCV001432644	pathogenic	Hypercholesterolemia, familial, 1	2019-01-22	criteria provided, single submitter	research
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000003934	SCV001653586	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000058917	SCV001715235	pathogenic	not provided	2022-01-05	criteria provided, single submitter	clinical testing	PP3
Revvity Omics, Revvity	RCV000003934	SCV002017130	pathogenic	Hypercholesterolemia, familial, 1	2022-06-03	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000003934	SCV002512251	pathogenic	Hypercholesterolemia, familial, 1	2021-12-08	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PS3 supporting, PS4 strong, PM2 moderate, PP1 strong, PP4 supporting
3billion	RCV000003934	SCV002573066	pathogenic	Hypercholesterolemia, familial, 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19361455). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000003736). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University Hospital Muenster	RCV002287321	SCV002577895	pathogenic	Hypercholesterolemia	2021-12-21	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PP5
Ambry Genetics	RCV002321469	SCV002607438	pathogenic	Cardiovascular phenotype	2022-09-12	criteria provided, single submitter	clinical testing	The c.313+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the LDLR gene. This mutation has been identified in both heterozygous and homozygous states in patients with classic familial hypercholesterolemia (FH) (Leren TP et al. Atherosclerosis. 1994;111(2):175-82; Hartgers ML et al. J Clin Lipidol 2018 Dec;12:390-396.e8; Ibarretxe D et al. Atherosclerosis, 2018 Nov;278:210-216; Chan ML et al. Mol Genet Genomic Med, 2018 Dec). 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). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000003934	SCV002811172	pathogenic	Hypercholesterolemia, familial, 1	2021-08-03	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000003934	SCV004176359	pathogenic	Hypercholesterolemia, familial, 1	2023-02-14	criteria provided, single submitter	clinical testing	The splice site variant c.313+1G>A in LDLR gene has been reported previously in heterozygous state in individuals affected with Familial hypercholesterolemia (Trinder M, et al., 2019, Zakharova FM, et al., 2005). Experimental evidence shows that this variant results in two mutant transcripts, one has skipping of exon 3 and the other has inclusion of intron 3. The transcript with skipping of exon 3 was demonstrated to have considerably reduced cell-surface LDLR and total amounts of internalized LDL, indicating that the variant LDLR is markedly dysfunctional (Cameron J, et al., 2009). The variant has 0.003% allele frequency in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has been submitted to ClinVar as Likely Benign, Likley Pathogenic, Pathogenic (multiple submissions).This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003944798	SCV004759052	pathogenic	LDLR-related condition	2024-01-16	criteria provided, single submitter	clinical testing	The LDLR c.313+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is a well-documented pathogenic variant for familial hypercholesterolemia (see for example Chan et al. 2018. PubMed ID: 30592178; Luirink et al. 2018. PubMed ID: 30795984; Jensen et al. 1999. PubMed ID: 10532689; Lombardi et al. 2000. PubMed ID: 10735632; Chmara et al. 2010. PubMed ID: 20145306; Mozas et al. 2004. PubMed ID: 15241806; Alonso et al. 2009. PubMed ID: 19318025; Lombardi et al. 1995. PubMed ID: 7616128). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000003934	SCV000024099	pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2014-09-25	no assertion criteria provided	clinical testing
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003934	SCV000268554	pathogenic	Hypercholesterolemia, familial, 1	2008-06-09	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003934	SCV000606074	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000003934	SCV000733814	pathogenic	Hypercholesterolemia, familial, 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.
Natera, Inc.	RCV000791438	SCV001456139	pathogenic	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000058917	SCV001925831	pathogenic	not provided		no assertion criteria provided	clinical testing