ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.337dup (p.Glu113fs)

dbSNP: rs752191968
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001201349 SCV000627036 pathogenic Familial hypercholesterolemia 2024-01-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu113Glyfs*17) 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 present in population databases (rs752191968, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 16314194). This variant is also known as 338insG. ClinVar contains an entry for this variant (Variation ID: 440560). For these reasons, this variant has been classified as Pathogenic.
UCSF Pediatric Lipid Clinic, University of California, San Francisco RCV000856583 SCV000998549 pathogenic Hypercholesterolemia 2019-09-25 criteria provided, single submitter clinical testing The p.E113fs variant segregates with elevated level of LDL-C in a family of 5 individuals. The allele frequency of this variant in the population is 0.00001 as reported by the ExAC database.
Ambry Genetics RCV002455981 SCV002616106 pathogenic Cardiovascular phenotype 2020-07-13 criteria provided, single submitter clinical testing The c.337dupG pathogenic mutation, located in coding exon 4 of the LDLR gene, results from a duplication of G at nucleotide position 337, causing a translational frameshift with a predicted alternate stop codon (p.E113Gfs*17). This alteration (referred to as 338insG) has been detected in a cohort of individuals reported to have familial hypercholesterolemia (Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8). This alteration was also detected in a Mexican family with familial hypercholesterolemia. In this family, two homozygous children were reported, and both had higher LDL-C and total cholesterol levels than their heterozygous parents and sibling (Wong KHY et al. Mol Genet Genomic Med, 2019 12;7:e1007). 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000508965 SCV000606088 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786351 SCV000925134 pathogenic not provided 2017-07-20 no assertion criteria provided provider interpretation p.Glu113Glyfs*17 (c.337dupG; also known as 338insG) in exon 4 of the LDLR gene (NM_000527.4) Given that this is a loss-of-function variant in a gene in which truncation is a known mechanism of disease, moderate case data and its rarity in the general population, we consider this variant disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant causes a shift in the reading frame of the LDLR gene, producing a truncated protein. Loss-of-function (truncated proteins) variants are a known mechanism of LDLR-associated familial hypercholesterolemia. The variant has been seen in at least 4 unrelated cases of familial hypercholesterolemia (not including this patient's family). There is moderate case data. This variant was present in 4 of 46 unrelated patients with familial hypercholesterolemia (Robles-Osorio et al, 2006), and was a "common" variant identified amongst 123 unrelated Mexican patients (per an abstract by Vazques Cardenas et al, 2015). This variant is not present in ClinVar; however another truncating variant at this codon (c.337G>T; p.Glu113Ter) is classified as pathogenic by four laboratories. The variant was reported online in 1 of 122,762 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 16,789 individuals of Latino descent (MAF=0.003%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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