ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.126C>A (p.Tyr42Ter)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237198 SCV000294475 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237198 SCV000588485 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001854883 SCV002239522 pathogenic Familial hypercholesterolemia 2021-11-29 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251028). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 23375686, 28965616). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr42*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017535 SCV004847633 pathogenic Homozygous familial hypercholesterolemia 2019-04-02 criteria provided, single submitter clinical testing The p.Tyr42X variant in LDLR has been reported in the heterozygous state in 3 individuals with familial hypercholesterolemia (FH) and in 1 individual with definite or probable FH who also had a loss of function variant in PCSK9 (Bertolini 2013, Jannes 2015, Pirillo 2017). This variant has also been reported in ClinVar (Variation ID: 251028) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 42, which is 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 based upon the predicted impact to the protein, absence from the general population and presence in affected individuals. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237198 SCV000606020 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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