Submissions for variant NM_000527.5(LDLR):c.1167G>A (p.Thr389=)

gnomAD frequency: 0.00052  dbSNP: rs139066906

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000495926	SCV004022386	likely benign	Hypercholesterolemia, familial, 1	2023-03-20	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1167G>A (p.Thr389=) variant is classified as likely benign for Familial Hypercholesterolemia by applying evidence codes: BP4, 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 needed. Functional data on splicing not available. A) not on limits B) does not create GT Variant is not predicted to alter splicing BP7 - Variant is synonymous and meets BP4.
PreventionGenetics, part of Exact Sciences	RCV000249917	SCV000304682	likely benign	not specified		criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000495926	SCV000583796	likely benign	Hypercholesterolemia, familial, 1	2022-03-30	criteria provided, single submitter	clinical testing	According to ClinGen VCEP consensus guidelines 2022, for LDLR variant classification, this variant previously estimated as "Likely Pathogenic" according to ACMG guidelines 2015 (potentially altering LDLR gene expression in silico; previously estimated as rare and found in several unrelated patients with a clinical scoring of Probable FH), may now be classified as "Likely Benign" according to updated guidelines : Synonymous, (BP7) and Revel score <0.5 (BP4).
Color Diagnostics, LLC DBA Color Health	RCV000775058	SCV000909158	likely benign	Familial hypercholesterolemia	2017-07-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000249917	SCV000919592	benign	not specified	2021-11-21	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1167G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 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 0.00012 in 250888 control chromosomes, predominantly at a frequency of 0.0013 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.1167G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia as a benign polymorphism (example, Wintjens_2016). This report does not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as benign/likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775058	SCV001003988	benign	Familial hypercholesterolemia	2024-02-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000495926	SCV001422915	likely benign	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	curation	The c.1167G>A variant in LDLR has been reported in 1 French individual and 1 individual from Pakistan with Familial Hypercholesterolemia (PMID: 26802169, 24338390), and has been identified in 0.1324% (33/24922) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139066906). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely benign and likely pathogenic in ClinVar (Variation ID: 256365). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BP4, BP7, PS4_Supporting (Richards 2015).
Ambry Genetics	RCV002327178	SCV002627004	likely benign	Cardiovascular phenotype	2015-02-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477868	SCV002773898	benign	not provided	2022-06-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000775058	SCV002086407	likely benign	Familial hypercholesterolemia	2020-05-19	no assertion criteria provided	clinical testing