ClinVar Miner

Submissions for variant NM_001195798.2(LDLR):c.820del (p.Thr274fs) (rs751122998)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Robarts Research Institute,Western University RCV000408879 SCV000484797 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Invitae RCV000775050 SCV000544641 pathogenic Familial hypercholesterolemia 2020-04-21 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 6 of the LDLR mRNA (c.820delA), causing a frameshift at codon 274. This creates a premature translational stop signal (p.Thr274Hisfs*96) and is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs751122998, ExAC 0.001%). This particular variant has been reported in the literature in individuals with familial hypercholesterolemia (PMID: 19026292, 27765764). ClinVar contains an entry for this variant (Variation ID: 369863). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000598567 SCV000709935 pathogenic not provided 2021-01-26 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19026292, 27765764, 30586733, 32041611, 33303402)
Color Health, Inc RCV000775050 SCV000909149 pathogenic Familial hypercholesterolemia 2020-02-25 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826195 SCV000967745 pathogenic Homozygous familial hypercholesterolemia 2020-12-11 criteria provided, single submitter clinical testing The p.Thr274HisfsX96 variant in LDLR has been reported in at least 6 individuals with familial hypercholesterolemia (FH), 2 of whom were suspected to have homozygous FH but an LDLR variant affecting the other copy was not identified (Kolansky 2008 PMID: 19026292, Wang 2016 PMID: 27765764, Gidding 2020 PMID: 232143996). It was also reported in 1 individual with early-onset myocardial infarction (Khera 2019 PMID: 30586733) and by other clinical laboratories in ClinVar (Variation ID 369863). Additionally, it has been identified in 0.002% (2/129158) of European chromosomes by gnomAD ( In vitro functional studies measuring LDL receptor activity in cultured skin fibroblasts show that this variant results in significantly reduced receptor activity (<2%, Kolansky 2008 PMID: 19026292). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 274 and leads to a premature termination codon 96 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting, PS3_Supporting.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000598567 SCV001134269 pathogenic not provided 2019-08-16 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000775050 SCV001448528 pathogenic Familial hypercholesterolemia 2020-11-16 criteria provided, single submitter clinical testing Variant summary: LDLR c.820delA (p.Thr274HisfsX96) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251428 control chromosomes (gnomAD). c.820delA has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Kolansky_2008) and early-onset myocardial infarction (Khera_2019). These data indicate that the variant may be associated with disease. One of these studies also reported experimental evidence evaluating an impact on protein function, and demonstrated <2% LDL receptor activity in patient derived fibroblast from two supposed homozygous patients, which is compatible with a receptor-negative status (Kolansky_2008). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000408879 SCV000606238 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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