ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1681C>T (p.Gln561Ter)

dbSNP: rs879254981
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238180 SCV000295571 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000238180 SCV000503382 pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 9 , family member = 1 with co-segregation
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238180 SCV000583860 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238180 SCV000599377 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Robarts Research Institute, Western University RCV000238180 SCV000782921 pathogenic Hypercholesterolemia, familial, 1 2018-01-02 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003391008 SCV004110373 pathogenic LDLR-related disorder 2023-03-21 criteria provided, single submitter clinical testing The LDLR c.1681C>T variant is predicted to result in premature protein termination (p.Gln561*). This variant is also described using legacy nomenclature as p.Gln540*, has been reported in the heterozygous and homozygous states in individuals with hypercholesterolemia (Webb et al. 1996. PubMed ID: 9026534; Amsellem et al. 2002. PubMed ID: 12436241). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic.
Invitae RCV003581630 SCV004298369 pathogenic Familial hypercholesterolemia 2023-08-14 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: 251965). This variant is also known as Gln540*. This premature translational stop signal has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 8292093, 32041611). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln561*) 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 RCV004017562 SCV004847697 pathogenic Homozygous familial hypercholesterolemia 2019-04-12 criteria provided, single submitter clinical testing The p.Gln561X variant in LDLR (also described as p.Gln440X in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), including one homozygous individual where the variant segregated with disease in at least 4 affected family members (Feher 1993, Webb 1996, Amsellem 2002, Vandrovcova 2013, ClinVar submission accessions: SCV000503382.1, SCV000583860.1). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 561, which is predicted to lead to a truncated or absent protein. Additionally, in vitro functional studies support an impact on protein function (Webb 1996). 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, PM2, PP1_Supporting, PS3_Supporting, PS4_Moderate.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000238180 SCV000606479 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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