ClinVar Genomic variation as it relates to human health

Pathogenic variant based on current evidence: This variant deletes one nucleotide after the translation start codon 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. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Loss-of-function truncation variants in the LDLR gene are known to be pathogenic (PMID: 20809525). Based on available evidence, this variant is classified as Pathogenic.

This frameshift variant is predicted to cause the premature termination of LDLR protein synthesis. It has been reported in individuals affected with familial hypercholesterolemia in the published literature (PMID: 31345425 (2019), 9259195 (1997)). Therefore, the variant is classified as pathogenic.

Variant summary: LDLR c.6delG (p.Trp4GlyfsX202) 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 was absent in 248678 control chromosomes (gnomAD). c.6delG has been reported in the literature in individuals affected with Familial Hypercholesterolemia (examples: Day_1997, Taylor_2007, and Hooper_2012). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Trp4Glyfs*202) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (FH) (PMID: 24075752). ClinVar contains an entry for this variant (Variation ID: 226303). For these reasons, this variant has been classified as Pathogenic.

The LDLR c.6del; p.Trp4Glyfs variant (rs875989888; ClinVar Variation ID: 226303) is reported in the literature in multiple individuals affected with familial hypercholesterolemia (FH; selected references: Day 1997, Sturm 2021, Taylor, 2007). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deletinga single nucleotide in exon 1, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several up- and downstream truncating variants have been described in individuals with FH and are considered pathogenic (Hobbs 1992). Based on available information, this variant is considered to be pathogenic. References: Day IN et al. Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. Hum Mutat. 1997;10(2):116-27. doi: 10.1002/(SICI)1098-1004(1997)10:2<116::AID-HUMU4>3.0.CO;2-I. PMID: 9259195. Hobbs HH et al. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445-66. PMID: 1301956. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665 Taylor A et al. Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia. Clin Genet. 2007 Jun;71(6):561-8. PMID: 17539906.

The c.6delG pathogenic mutation, located in coding exon 1 of the LDLR gene, results from a deletion of one nucleotide at position 6, causing a translational frameshift with a predicted alternate stop codon (p.W4Gfs*202). This alteration has been previously reported in familial hypercholesterolemia cohorts (Hooper AJ et al. Atherosclerosis. 2012;224(2):430-4; Faiz F et al. Atherosclerosis. 2013;230(2):249-55). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28964736, 22883975, 17539906, 24075752, 34037665, 9259195)