ClinVar Miner

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

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Total submissions: 7
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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 2019-10-30 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 2018-01-22 criteria provided, single submitter clinical testing The c.820delA pathogenic variant in the LDLR gene has been reported previously in one French Canadian female diagnosed with FH at 3-years-old with LDLR activity less than 2% of wild type (Kolansky et al., 2008). This individual is suspected to have homozygous FH, however a second LDLR variant was not identified (Kolansky et al., 2008). Furthermore, this variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.820delA variant causes a shift in reading frame starting at codon threonine 274, changing it to a histidine, and creating a premature stop codon at position 96 of the new reading frame, denoted p.Thr274HisfsX96. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene.
Color 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 2018-02-20 criteria provided, single submitter clinical testing The p.Thr274fs variant in LDLR has been reported in the heterozygous state in 2 individuals with familial hypercholesterolemia (Kolansky 2008). This variant has also been identified in 2/126720 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs751122998). Please note that this frequency is low enough to be consistent with the frequency of FH in the general population. This variant is predicted to cause a frameshift, whi ch 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 t hen predicted to lead to a truncated or absent protein. Heterozygous loss of LDL R function is an established disease mechanism in familial hypercholesterolemia. Additionally, in vitro functional studies demonstrate that this variant results in reduced protein activity (Kolansky 2008). In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia based on predicted impact to the protein and functional studies. ACMG/AMP Criteria ap plied: PVS1; PM2; PMS3_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.
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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