ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1359-5C>G (rs531005522)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238316 SCV000295389 pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238316 SCV000322946 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/75 normolipidaemic Portuguese controls
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844742 SCV000731830 likely pathogenic Familial hypercholesterolemia - homozygous 2017-10-31 criteria provided, single submitter clinical testing The c.1359-5C>G variant in LDLR has been reported in at least 2 individuals with familial hypercholesterolemia (FH) and segregated with disease in 4 affected re latives from 2 families (Bourbon 2009, Medeiros 2014, ClinVar: Variation ID 2518 08). However, it was not identified in an additional affected relative, (Bourbon 2009, Medeiros 2014). The c.1359-C>G variant has also been identified in 2/1112 74 of European chromosomes by the Genome Aggregation Database (GnomAD, http://gn omad.broadinstitute.org; dbSNP rs531005522). This variant is located in the 3' s plice region. Amplification of patient mRNA by RT-PCR has shown that this varia nt causes retention of intron 9 and is predicted to result in a frameshift, whic h alters the protein's amino acid sequence beginning at position 453 and leads t o a premature termination codon 1 amino acid downstream (Bourbon 2009). This alt eration is then predicted to lead to a truncated or absent protein. In summary, although additional studies are required to fully establish its clinical signifi cance, the c.1359-5C>G variant is likely pathogenic.

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