ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.520G>T (p.Glu174Ter)

dbSNP: rs777326720
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Robarts Research Institute, Western University RCV000408802 SCV000484758 likely pathogenic Hypercholesterolemia, familial, 1 criteria provided, single submitter clinical testing
Ambry Genetics RCV002348123 SCV002645967 pathogenic Cardiovascular phenotype 2021-05-21 criteria provided, single submitter clinical testing The p.E174* pathogenic mutation (also known as c.520G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 520. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. This alteration has been reported in a familial hypercholesterolemia (FH) cohort (Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445). In addition, 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017597 SCV004847687 likely pathogenic Homozygous familial hypercholesterolemia 2019-04-16 criteria provided, single submitter clinical testing The p.Glu174X variant in LDLR has been reported in the heterozygous state in 1 individual with coronary artery disease (Khera 2016) and 1 individual with familial hypercholesterolemia (FH; ClinVar submission accession: SCV000484758.1). It has also been identified in 0.007% (2/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 174, which is 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, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PM2.

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