Submissions for variant NM_000527.4(LDLR):c.694+2T>C

dbSNP: rs200238879

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003936	SCV000294919	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000003936	SCV000503226	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family member = 1
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003936	SCV000583730	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000003936	SCV000607495	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201185	SCV001372245	pathogenic	Familial hypercholesterolemia	2020-06-15	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.694+2T>C 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 causes abnormal mRNA splicing (Gudnason_1997). The variant was absent in 244508 control chromosomes (gnomAD). c.694+2T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Gudnason_1997, Wintjens_2016). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002362560	SCV002661875	pathogenic	Cardiovascular phenotype	2019-06-13	criteria provided, single submitter	clinical testing	The c.694+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 4 in the LDLR gene. This mutation (also described as rs200238879) has been reported in multiple individuals with familial hypercholesterolemia (FH) and coronary artery disease with elevated cholesterol levels, particularly in Icelandic cohorts, where it was traced to a shared ancestor among several families (Gudnason V et al. Hum. Mutat., 1997;10:36-44; Gretarsdottir S et al. PLoS Genet., 2015 Sep;11:e1005379; Helgadottir A et al. Nat. Genet., 2016 06;48:634-9). Limited mRNA analysis showed the loss of the native donor splice site led to intron inclusion in at least some transcripts (Gudnason V et al. Hum. Mutat., 1997;10:36-44). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201185	SCV003442712	pathogenic	Familial hypercholesterolemia	2024-04-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with familial hypercholesterolemia (PMID: 9222758). It is commonly reported in individuals of Icelandic ancestry (PMID: 9222758, 26327206). This variant is also known as I4T+2C. ClinVar contains an entry for this variant (Variation ID: 3738). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000003936	SCV004848470	pathogenic	Hypercholesterolemia, familial, 1	2020-09-04	criteria provided, single submitter	clinical testing	The c.694+2T>C variant in LDLR has been previously reported as a founder mutation causative for familial hypercholesterolemia in the Icelandic population, as it was identified via haplotype analysis in several affected probands who shared a common ancestor and was reported to segregate with disease (Gudnason 1997 PMID: 9222758). This variant has also been shown to have a statstically significant association to increased non-HDL cholesterol levels and increased risk for coronary artery disease (Helgadottir 2016 PMID: 27135400, Gretarsdottir 2015 PMID: 26327206). It has been reported in ClinVar (Variation ID 3738) but was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, RT-PCR performed on blood cells from a patient heterozygous for this variant revealed abnormal mRNA containing intron 4 sequence (Gudnason 1997 PMID: 9222758). Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant familial hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP criteria applied: PP1_Strong, PM2, PVS1_Moderate, PS4_Moderate, PS3_Supporting.
OMIM	RCV000003936	SCV000024101	pathogenic	Hypercholesterolemia, familial, 1	1997-01-01	no assertion criteria provided	literature only
deCODE genetics, Amgen	RCV000003936	SCV004022252	pathogenic	Hypercholesterolemia, familial, 1	2023-07-21	no assertion criteria provided	research	The variant NM_000527.5:c.694+2T>C (chr19:11105602) in LDLR was detected in 41 heterozygotes out of 58K WGS Icelanders (MAF= 0,035%). Following imputation in a set of 166K Icelanders (80 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 2.19, P= 1.02e-52), Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 1.99, P= 1.81e-44), pure hypercholesterolaemia using 1515 cases and 283197 controls (OR= 25.81, P= 8.16e-12) and myocardial infarction using 25692 cases and 320832 controls (OR= 4.78, P= 4.69e-06). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic.