ClinVar Miner

Submissions for variant NM_001195798.2(LDLR):c.1415_1418dup (p.Gln474fs) (rs879254892)

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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 RCV000238471 SCV000295417 pathogenic Familial hypercholesterolemia 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 RCV000238471 SCV000503345 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 3 , family members = 4
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238471 SCV000599373 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Iberoamerican FH Network RCV000238471 SCV000748148 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
GeneDx RCV000657895 SCV000779659 pathogenic not provided 2018-06-04 criteria provided, single submitter clinical testing The c.1415_1418dupACAT pathogenic variant in the LDLR gene, also reported as FH Savona-1, c.1418_1419insACAT, and FS453Term515 due to the use of alternate nomenclature, is a common variant identified in at least 190 individuals with familial hypercholesterolemia (FH) from 50 unrelated Italian familes (Sun et al., 1998; Bertolini et al., 2000; Pisciotta et al., 2012). Furthermore, the c.1415_1418dupACAT variant has not been observed in large population cohorts (Lek et al., 2016). The c.1415_1418dupACAT variant causes a shift in reading frame starting at codon glutamine 474, changing it to a histidine, and creating a premature stop codon at position 63 of the new reading frame, denoted p.Gln474HisfsX63. 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, and loss of function is a known mechanism of disease for this gene (Stenson et al., 2014).

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