Submissions for variant NM_000527.5(LDLR):c.1187-10G>A

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211627	SCV000295273	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211627	SCV000484784	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	RCV000211627	SCV000503311	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 , family member = 2
Invitae	RCV000588170	SCV000544644	pathogenic	Familial hypercholesterolemia	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. This variant is present in population databases (rs765696008, gnomAD 0.006%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 11668627, 12436241, 20145306, 21865347, 24075752, 26077743). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 226349). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LDLR function (PMID: 21865347). 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.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211627	SCV000583801	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211627	SCV000588563	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211627	SCV000607571	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588170	SCV000697187	pathogenic	Familial hypercholesterolemia	2017-03-28	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1187-10G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a disease-causing outcome for this variant. 5/5 splice prediction tools predict the creation of a cryptic splice site 8bp upstream of the canonical splice site at the exon-intron junction. A functional study that assayed splicing defects via cDNA analysis in a family affected by familial hypercholesterolemia showed that a heterozygous individual expresses both the WT allele as well as the variant allele (which includes the 8bp of retained intronic sequence), and a severely affected homozygous individual who expresses no detectable WT transcript (Sun_Sci Rep_2015). Additionally, another study analyzed residual LDLR activity in B- and T-lymphocytes in FH patients compared to control individuals and found that heterozygous patients have approximately half of LDLR activity of control individuals via flow cytometry experiments (Romano_JLR_2011), which supports the hypothesis that the variant is a null allele. This variant was found in the large control database ExAC at a frequency of 0.0000417 (5/119944 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). In addition, the observations of the variant in the ExAC dataset needs to be cautiously considered due to the cohort containing individuals that could harbor a LDLR phenotype. Furthermore, a publication, Sun_2015, shows the variant to cosegregate with disease in a large FH family, including the proband, who was homozygous for the variant and had a significantly elevated lipid level. Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000588170	SCV000909159	pathogenic	Familial hypercholesterolemia	2023-02-09	criteria provided, single submitter	clinical testing	This variant changes a single nucleotide in intron 8 of the LDLR gene and is predicted to create a new splice acceptor, eight nucleotides upstream from the canonical splice acceptor site. A RNA study with cells from a homozygous subject has confirmed that the usage of the new splice acceptor resulted in the mRNA that included the last eight nucleotides of intron 8 (PMID: 26077743). This creates a frameshift and premature translational stop signal and is expected to result in an absent or non-functional protein product. This variant has been identified in multiple Caucasian individuals diagnosed with familial hypercholesterolemia (PMID: 11668627, 12436241, 20145306, 21865347, 24075752). In a large Chinese family, this variant segregated with hypercholesterolemia in nine heterozygous individuals and one homozygous child who showed severe phenotype (PMID: 26077743). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 36325061). This variant has been identified in 7/250138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211627	SCV001432548	likely pathogenic	Hypercholesterolemia, familial, 1	2019-01-21	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000786346	SCV002046469	pathogenic	not provided	2020-12-08	criteria provided, single submitter	clinical testing	This variant has been reported in multiple individuals affected with familial hypercholesterolemia (FH), including one homozygous individual with severe phenotype (PMIDs: 11668627 (2001), 12436241 (2002), 16205024 (2005), 20145306 (2010), 24075752 (2013), and 26077743 (2015)). In addition, cell-based functional studies report this variant is damaging to LDLR protein activity by activating a cryptic splice acceptor site which leads to early termination of LDLR mRNA translation (PMIDs: 19208450 (2009), 21865347(2011), and 26077743 (2015)). Furthermore, this variant was shown to cosegregate with disease in a large family affected with familial hypercholesterolemia (FH) (PMID: 26077743 (2015)). Therefore, the variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000786346	SCV002103277	pathogenic	not provided	2021-05-20	criteria provided, single submitter	clinical testing	PVS1, PS3_moderate, PM3_supporting, PS4_moderate
3billion	RCV000211627	SCV002521688	likely pathogenic	Hypercholesterolemia, familial, 1	2022-05-22	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%). Each parent is heterozygous for the variant. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26077743, 21865347) In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 1.00). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000226349). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002336589	SCV002634909	pathogenic	Cardiovascular phenotype	2022-04-05	criteria provided, single submitter	clinical testing	The c.1187-10G>A intronic pathogenic mutation results from a G to A substitution 10 nucleotides upstream from coding exon 9 in the LDLR gene. This mutation has been described in individuals affected with familial hypercholesterolemia (FH) from different populations (Hooper AJ et al, Atherosclerosis 2012;224(2):430-4; Punzalan FE et al, J. Atheroscler. Thromb. 2005;12(5):276-83; Wang J et al, Hum. Mutat. 2001; 18(4):359; Amsellem S et al, Hum. Genet. 2002;111(6):501-10; Romano M et al, J. Lipid Res. 2011;52(11):2095-100; Sun LY et al, Sci Rep 2015;5:11380). LDLR protein showed reduced activity levels in patient derived lymphocytes in vitro (Romano M et al, J. Lipid Res. 2011;52(11):2095-100 ). This variant was described to co-segregate with FH phenotype in a Chinese family and cDNA analysis revealed that this variant caused abnormal splicing (Sun LY et al, Sci Rep 2015;5:11380). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000211627	SCV003819531	pathogenic	Hypercholesterolemia, familial, 1	2022-11-11	criteria provided, single submitter	clinical testing
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211627	SCV000268602	pathogenic	Hypercholesterolemia, familial, 1	2008-06-05	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211627	SCV000606346	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786346	SCV000925124	pathogenic	not provided	2016-04-19	no assertion criteria provided	provider interpretation	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 showed that the following variant was identified: c.1187-10G>A in the LDLR gene (NM_000527.4) The lab classifies this variant as pathogenic. Given the strong case data we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 13 unrelated cases of familial hypercholesterolemia (not including this patient's family), this is significant case data supporting the pathogenicity of this variant. Chmara et al., 2009, identified the c.1187-10G>A LDLR variant in 4 of 378 patients with familial hypercholesterolemia. They predicted this variant to be pathogenic and state that it resulted in deletion of consensus acceptor site and formation of a de novo acceptor site at 1187-8. Hooper et al., 2012, performed mutation testing of LDLR in 343 patients with possible, probable, or definite FH and found the c.1187-10G>A variant in 2 individuals in this cohort. Sun et al., 2015, identified a Chinese family with FH and found that the c.1187-10G>A variant segregated with disease in the family. It was also found in a homozygous state in one affected individual in the family with severe FH who had high cholesterol as well as tendon xanthomas. The c.1187-10G>A variant was not identified in 39 sporadic FH subjects or 288 healthy Chinese control subjects. They also gentoyped the cDNA of LDLR and found that the variant activated cryptic splice sites, resulting in a transcript that included the last eight nucleotides of intron 8 in the mRNA. Punzalan et al., 2005, performed genetic testing of LDLR for 60 unrelated Filipino patients with a clinical diagnosis of FH. They found the c.1187-10G>A mutation in 2 out of the 60 patients. Amsellem et al., 2002, performed genetic testing of 110 FH patients from an admixed population. They identified the c.1187-10G>A mutation in 2 patients in this cohort. Romano et al., 2011, identified the c.1187-10G>A variant in 2 individuals with FH. These patients had reduced LDLR residual activity on EBV-transformed B-lymphocytes as well as reduced LDLR residual activity on stimulated T-lymphocytes. Four web-based tools were used to determine whether the c.1187-10G>A variant affected the splice site. ASSP, HSF, and NetGene2 all identified a cryptic donor site generated by the c.1187-10G>A variant. All four software tools reported that the confidence scores of the cryptic donor site are higher than the natural splice site. The variant has not been seen in laboratory controls, published controls or individuals from publicly available population datasets. There is no variation at c.1187-10G>A listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/19/16).