ClinVar Miner

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

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Total submissions: 7
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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 1 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 1 2016-03-01 criteria provided, single submitter research 0/75 normolipidaemic Portuguese controls
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844742 SCV000731830 uncertain significance not specified 2021-01-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The c.1359-5G>C variant in LDLR has been reported in 2 Portuguese individuals with Familial hypercholesterolemia (FH) and segregated with disease in 2 affected individuals from 2 families, although in at least 1 of the families segregation was incomplete and 2 affected individuals were not carriers of this variant (Bourbon 2009 PMID: 19411563, Medeiros 2014 PMID:24627126, Gaspar 2019 PMID: 30876530). It has also been identified in 0.002% (2/113226) of European chromosomes by gnomAD ( This variant has also been reported in ClinVar (Variation ID 251808). This variant is located in the 3' splice region. Computational tools do not predict a splicing impact, though this information is not predictive enough to rule out pathogenicity. Amplification of patient mRNA by RT-PCR has shown that this variant causes retention of intron 9 and is predicted to result in a frameshift, which alters the protein's amino acid sequence beginning at position 453 and leads to a premature termination codon 1 amino acid downstream (Bourbon 2009 PMID: 19411563). This alteration is then predicted to lead to a truncated or absent protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PS3_Supporting, PS4_Supporting.
Invitae RCV001052016 SCV001216204 uncertain significance Familial hypercholesterolemia 2019-12-04 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 19411563). ClinVar contains an entry for this variant (Variation ID: 251808). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 19411563). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000238316 SCV001286369 uncertain significance Familial hypercholesterolemia 1 2017-10-12 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Health, Inc RCV001052016 SCV001347905 likely pathogenic Familial hypercholesterolemia 2019-11-15 criteria provided, single submitter clinical testing
GeneDx RCV001568174 SCV001791999 likely pathogenic not provided 2021-03-22 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 31447099, 24627126, 27821657, 30876530, 20828696, 24075752, 20964105, 22881376, 19411563)

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