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

dbSNP: rs143872778

Total submissions: 16

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).
Labcorp Genetics (formerly Invitae), Labcorp	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
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000210239	SCV000606531	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003927891	SCV004737436	likely benign	LDLR-related disorder	2020-01-02	no assertion criteria provided	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).