ClinVar Miner

Submissions for variant NM_001195798.2(LDLR):c.2478del (p.Val827fs) (rs747344293)

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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 RCV000237345 SCV000296016 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237345 SCV000599419 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
GeneDx RCV000598936 SCV000709936 pathogenic not provided 2018-02-23 criteria provided, single submitter clinical testing The c.2478delC pathogenic variant in the LDLR gene was paternally inherited in a Chinese child with severe familial hypercholesterolemia and a second maternally inherited variant in the LDLR gene; of note, the heterozygous father was reported to have elevated cholesterol (Sun et al., 1994). This variant causes a shift in reading frame starting at codon valine (Val) 827, changing it to a serine (Ser), and creating a premature stop codon at position 102 of the new reading frame, denoted p.Val827SerfsX102. This pathogenic variant is located in the penultimate exon and is predicted to result in an abnormal protein product with the last 34 amino acid residues replaced by 101 incorrect amino acid residues. Functional studies show that the c.2478delC variant results in either no detectable LDLR protein, or low levels of LDLR protein that is unable to bind the LDL ligand (Sun et al., 1994). Other frameshift variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014), including a different downstream frameshift variant (c.2509delC) predicted to use the same termination codon as the c.2478delC variant. Furthermore, the c.2478delC variant has not been observed in large population cohorts (Lek et al., 2016).
Robarts Research Institute,Western University RCV000237345 SCV000782943 pathogenic Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Invitae RCV001050453 SCV001214561 pathogenic Familial hypercholesterolemia 2019-03-11 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the LDLR gene (p.Val827Serfs*102). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acids of the LDLR protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hypercholesterolemia (PMID: 7903864). ClinVar contains an entry for this variant (Variation ID: 252342). This variant has been reported to affect LDLR protein expression (PMID: 7903864). This variant disrupts the C-terminus of the LDLR protein. Other variant(s) that disrupt this region (p.Ser849*) have been determined to be pathogenic (PMID: 26892515, 11933210, 22509010, 2088165). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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