ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1836C>T (p.Ala612=)

dbSNP: rs143872778
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000210239 SCV004022373 likely benign Hypercholesterolemia, familial, 1 2023-04-28 reviewed by expert panel curation The NM_000527.5(LDLR):c.1836C>T (p.Ala612=) variant is classified as likely benign for Familial Hypercholesterolemia by applying evidence code BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4 - No REVEL, splicing evaluation required. Functional data on splicing not available. - Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. - There is a GT nearby. MES scores: variant cryptic = -16.82, wt cryptic = -12.61, canonical donor = 4.48. Ratio variant cryptic/wt cryptic: -16.82/-12.61 = 1.33 --- it is above 1.1 Ratio variant cryptic/canonical donor: -16.82/4.48 = -3.75 --- it is not above 0.9 Variant is not predicted to alter splicing. BP7 - Variant is synonymous and meets BP4.
Cardiovascular Biomarker Research Laboratory, Mayo Clinic RCV000210239 SCV000266318 uncertain significance Hypercholesterolemia, familial, 1 2015-08-31 criteria provided, single submitter research MAF =<0.3%, LDL-C >=160 mg/dL
LDLR-LOVD, British Heart Foundation RCV000210239 SCV000295690 likely benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Illumina Laboratory Services, Illumina RCV000210239 SCV000410538 uncertain significance Hypercholesterolemia, familial, 1 2016-06-14 criteria provided, single submitter clinical testing The c.1836C>T (p.Ala612Ala) variant has been reported in two studies and is found in a total of eight familial hypercholesterolemia patients in a heterozygous state (Widhalm et al. 2007; Chmara et al. 2010). In silico analysis of this variant predicted no effect on consensus splice sites and overall non-pathogenicity (Chmara et al. 2010; Usifo et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00034 in the European (Non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Ala612Ala variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial hypercholesterolemia.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000456101 SCV000539509 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is a silent variant in LDLR. It is classified as DM in HGMD. This variant has been reported in 7 patients with familial hypercholesterolemia in one study (Widhalm 2007). This variant is classified in ClinVar with 1 star as VUS by Mayo Clinic and as Likely Benign by British Heart Foundation. The variant has a Max MAF of 0.03% in ExAC (23 alleles) and 0.03% in gnomAD (43 alleles).
Invitae RCV000771188 SCV000556782 likely benign Familial hypercholesterolemia 2024-01-31 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000210239 SCV000583890 likely pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000456101 SCV000697212 likely benign not specified 2023-08-21 criteria provided, single submitter clinical testing Variant summary: LDLR c.1836C>T alters a non-conserved nucleotide resulting in a synonymous change. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 251468 control chromosomes (i.e., 46 heterozygotes; gnomAD v2.1 Exomes dataset). This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease (0.00018 vs 0.001), allowing no conclusion about variant significance. The variant, c.1836C>T, has been reported in the literature in individuals affected with premature atherosclerosis and/or hypercholesterolaemia (e.g., Widhalm_2007, Chmara_2010, Saracoglu_2018). These reports do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20145306, 28145427, 22881376, 17347910, 29870584). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (benign, n = 1; likely benign, n = 5; VUS, n = 4; likely pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV001705182 SCV000728649 likely benign not provided 2019-09-04 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22881376, 28145427, 17347910, 20145306, 32719484)
Color Diagnostics, LLC DBA Color Health RCV000771188 SCV000903169 likely benign Familial hypercholesterolemia 2017-07-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002408911 SCV002710917 benign Cardiovascular phenotype 2021-05-26 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
New York Genome Center RCV000210239 SCV003925119 uncertain significance Hypercholesterolemia, familial, 1 2022-04-22 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001705182 SCV004033641 likely benign not provided 2024-01-01 criteria provided, single submitter clinical testing LDLR: BP4, BP7
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001705182 SCV004563125 likely benign not provided 2023-08-17 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003927891 SCV004737436 likely benign LDLR-related disorder 2020-01-02 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000210239 SCV000606531 benign Hypercholesterolemia, familial, 1 no assertion criteria provided research

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