ClinVar Genomic variation as it relates to human health

Variant summary: LDLR c.820delA (p.Thr274HisfsX96) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251428 control chromosomes (gnomAD). c.820delA has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Kolansky_2008) and early-onset myocardial infarction (Khera_2019). These data indicate that the variant may be associated with disease. One of these studies also reported experimental evidence evaluating an impact on protein function, and demonstrated <2% LDL receptor activity in patient derived fibroblast from two supposed homozygous patients, which is compatible with a receptor-negative status (Kolansky_2008). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19026292, 27765764, 30586733, 32041611, 33303402)

This variant deletes a single nucleotide in exon 6 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 19026292, 27765764, 32143996). This variant has been identified in 2/282836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

ClinVar contains an entry for this variant (Variation ID: 369863). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 19026292, 27765764). This variant is present in population databases (rs751122998, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Thr274Hisfs*96) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).

The c.820del (p.Thr274Hisfs*96) variant of the LDLR gene introduces a premature translation termination codon resulting in an absent or disrupted protein product. The variant has been reported in heterozygous status in at least five individuals who fulfill the clinical criteria of familial hypercholesterolemia (FH) (PMID: 27765764, 32143996), and in 1/2081 individual from an early-onset myocardial infarction cohort while absent in 3761 controls (PMID: 30586733). This variant in homozygous status has been detected in two individuals with severe FH (>500mg/dL) and in-vitro functional studies using patients derived skin fibroblasts showed significantly reduced LDLR (<2%) activity (PMID: 19026292). Loss-of-function variants in LDLR are well known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 15199436? 9698020, 16389549, 17765246, 17935672, 33740630) and by several ClinVar submitters (ClinVar ID: 251478, 251475). This variant is found to be rare (2/282836; 0.000007) in the general population database (gnomAD) and interpreted as pathogenic by multiple submitters in the ClinVar (ClinVar ID: 369863). Therefore, the c.820del (p.Thr274Hisfs*96) variant in the LDLR gene is classified as pathogenic.

The p.Thr274HisfsX96 variant in LDLR has been reported in at least 6 individuals with familial hypercholesterolemia (FH), 2 of whom were suspected to have homozygous FH but an LDLR variant affecting the other copy was not identified (Kolansky 2008 PMID: 19026292, Wang 2016 PMID: 27765764, Gidding 2020 PMID: 232143996). It was also reported in 1 individual with an early-onset myocardial infarction (Khera 2019 PMID: 30586733) and by other clinical laboratories in ClinVar (Variation ID 369863). Additionally, it has been identified in 0.002% (2/129158) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies measuring LDL receptor activity in cultured skin fibroblasts show that this variant results in significantly reduced receptor activity (<2%, Kolansky 2008 PMID: 19026292). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 274 and leads to a premature termination codon 96 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting, PS3_Supporting.

The c.820delA pathogenic mutation, located in coding exon 6 of the LDLR gene, results from a deletion of one nucleotide at position 820, causing a translational frameshift with a predicted alternate stop codon (p.T274Hfs*96). This mutation has been identified in several individuals with hypercholesterolemia and reported in association with reduced low density lipoprotein receptor activity (Kolansky DM et al. Am J Cardiol. 2008;102(11):1438-43; Wang J et al. Arterioscler. Thromb. Vasc. Biol., 2016 Dec;36:2439-2445). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.