ClinVar Genomic variation as it relates to human health

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).

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the LDLR protein in which other variant(s) (p.Ser849*) have been determined to be pathogenic (PMID: 2088165, 11933210, 22509010, 26892515). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that this premature translational stop signal affects LDLR function (PMID: 7903864). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 252342). This premature translational stop signal has been observed in individual(s) with hypercholesterolemia (PMID: 7903864). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val827Serfs*102) in the LDLR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the LDLR protein.

The c.2478delC (p.V827Sfs*102) alteration, located in exon 17 (coding exon 17) of the LDLR gene, consists of a deletion of one nucleotide at position 2478, causing a translational frameshift with a predicted alternate stop codon after 102 amino acids. This alteration occurs at the 3' terminus of theLDLR gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 67 amino acids. This frameshift impacts the last 34 amino acids(~4%) of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, referred to as a 1-bp deletion in codon 805, was reported in a family with familial hypercholesterolemia and in vitro studies suggested that it would affect LDLR protein expression or stability (Sun, 1994). Based on the available evidence, this alteration is classified as pathogenic.