ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.678_681dup (p.Glu228Ter)

dbSNP: rs2077282376
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001389014 SCV001590218 pathogenic Familial hypercholesterolemia 2022-02-10 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1075416). This premature translational stop signal has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 30293936, 33740630, 34037665). This sequence change creates a premature translational stop signal (p.Glu228*) 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).
Ambry Genetics RCV004995735 SCV005609331 pathogenic Cardiovascular phenotype 2024-10-10 criteria provided, single submitter clinical testing The c.678_681dupTGAC pathogenic mutation, located in coding exon 4 of the LDLR gene, results from a duplication of TGAC at nucleotide position 678, causing a translational frameshift with a predicted alternate stop codon (p.E228*). This variant has been reported in association with familial hypercholesterolemia (FH) (Han SM et al. PLoS One, 2015 May;10:e0126706; Chiou KR et al. J Clin Lipidol, 2017 Jan;11:386-393.e6; Reiman A et al. Ann Clin Biochem, 2016 Nov;53:654-662; Martín-Campos JM et al. J Clin Lipidol, 2018 Sep;12:1452-1462; Leren TP et al. Atherosclerosis, 2021 Apr;322:61-66; Sturm AC et al. JAMA Cardiol, 2021 Aug;6:902-909). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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