ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.68-1G>C

dbSNP: rs879254397
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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 RCV000238079 SCV000294449 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238079 SCV000599310 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
GeneDx RCV000521979 SCV000617498 pathogenic not provided 2017-10-23 criteria provided, single submitter clinical testing The c.68-1 G>C variant in the LDLR gene has been identified in a homozygous state in one individual with severe hypercholesterolemia and tendon xnathomas. Three maternal relatives were heterozygous for the variant and had serum choleterol levels consistent with heterozygous FH (HeFH). Cultured fibroblasts from the proband showed null LDLR protein synthesis. Additionally, functional mRNA studies supported destruction of the canonical splice acceptor site in intron 1, and utilization of a cryptic acceptor site downstream of exon 2 (Maruyama et al. 1998). This variant was also published in an individual with clinical HeFH, who also harbored a rare variant in the PCSK9 gene (Ohta et al., 2016). This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the LDLR gene, including c.68-2 A>T and c.68-2 A>G, have been reported in HGMD in association with FH (Stenson et al., 2014). Furthermore, the c.68-1 G>C variant is not observed in large population cohorts (Lek et al., 2016).
Ambry Genetics RCV002365237 SCV002664186 pathogenic Cardiovascular phenotype 2018-06-21 criteria provided, single submitter clinical testing The c.68-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 2 of the LDLR gene, and is located in the region of the ligand binding 1 domain. This variant has been reported in a homozygous Japanese female from consanguineous parents, who had hypercholesterolemia and tendon xanthomas, as well as in an Italian family with heterozygous familial hypercholesterolemia, and in a Japanese female with hypercholesterolemia who also harbored a PCSK9 variant (Maruyama T et al. Hum. Mutat., 1998;11:480-1; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Ohta N et al. J Clin Lipidol 2016 Jan;10:547-555.e5). Limited functional studies in fibroblasts from the homozygous individual reportedly showed no LDLR protein was produced, while RNA studies suggested use of a downstream cryptic acceptor site caused a frameshift leading to a premature stop codon (Maruyama T et al. Hum. Mutat., 1998;11:480-1). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV002519837 SCV003256922 pathogenic Familial hypercholesterolemia 2023-11-28 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 10200052; Invitae). ClinVar contains an entry for this variant (Variation ID: 251005). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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