ClinVar Miner

Submissions for variant NM_001195798.2(LDLR):c.1476_1477CT[1] (p.Ser493fs) (rs869025453)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208069 SCV000264003 pathogenic Familial hypercholesterolemia 1 2015-07-02 criteria provided, single submitter clinical testing
LDLR-LOVD, British Heart Foundation RCV000208069 SCV000295462 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000208069 SCV000484798 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000208069 SCV000503356 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 4 , family members = 2 with co-segregation
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000208069 SCV000540905 pathogenic Familial hypercholesterolemia 1 2017-03-27 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000208069 SCV000583837 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
GeneDx RCV000522258 SCV000617510 pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing The c.1478_1479delCT pathogenic variant in the LDLR gene has been reported multiple times in association with FH. Affected individuals were of various ethnic backgrounds, and included those with Dutch, Italian, German, Danish, and Armenian ancestry (Chmara et al., 2010; Fouchier et al., 2001; Bertolini et al., 1999; Schuster et al., 1995; Damgaard et al. 2005; Jensen et al., 1996; Cavanaugh et al., 1994; Minicocci et al., 2017). This two base pair deletion has been published with several names in the literature, including FH-Sydney 2, FH-Frosinone, and FH-Yrmeih (Cavanaugh et al., 1994; Fokkema et al., 2005). Additionally, the c.1478_1479delCT is also classified as a pathogenic variant in ClinVar by several clinical laboratories (SCV000264003.1, SCV000503356.1, SCV000540905.1, SCV000583837.1, SCV000752413.1; Landrum et al., 2016). Furthermore, the c.1478_1479delCT variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016). Located in the EGF spacer, this variant causes a shift in reading frame starting at codon serine 493, changing it to a cysteine, and creating a premature stop codon at position 42 of the new reading frame, denoted p.Ser493CysfsX42. 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 pathogenic frameshift variants in the LDLR gene have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014).
Invitae RCV000780377 SCV000752413 pathogenic Familial hypercholesterolemia 2019-12-12 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotide from exon 10 of the LDLR mRNA (c.1478_1479delCT), causing a frameshift at codon 493. This creates a premature translational stop signal (p.Ser493Cysfs*42) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic. This particular variant has been reported in the literature in several individuals and families affected with familial hypercholesterolemia (PMID: 7866407, 11810272, 21865347, 20045108, 20145306). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000780377 SCV000917580 pathogenic Familial hypercholesterolemia 2018-05-07 criteria provided, single submitter clinical testing Variant summary: LDLR c.1478_1479delCT (p.Ser493CysfsX42) 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 (eg. c.1686G>A, p.Trp562X; c.2043C>A, p.Cys681X; c.2061dupC, p.Asn688fsX29). The variant allele was found at a frequency of 3.2e-05 in 30908 control chromosomes (gnomAD). The variant, c.1478_1479delCT, has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Cavanaugh_1994, Jensen_1996, Fouchier_2001, Romano_2011, Kusters_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing a 10%-30% of normal LDL uptake activity associated with this variant (Romano_2011). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and 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 RCV000208069 SCV000606441 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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