ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1860G>A (p.Trp620Ter)

dbSNP: rs875989933
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237143 SCV000295721 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Invitae RCV000775248 SCV000544648 pathogenic Familial hypercholesterolemia 2022-12-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp620*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 252089). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 25846081). This variant is not present in population databases (gnomAD no frequency).
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237143 SCV000583899 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000237143 SCV000839977 pathogenic Hypercholesterolemia, familial, 1 2017-05-17 criteria provided, single submitter clinical testing The c.1860G>A (p.Trp620*) variant in the LDLR gene has been reported in one patient with autosomal dominant hypercholesterolemia [PMID 20809525]. This variant also segregated with the phenotype within the reported proband’s family. The c.1860G>A change creates a premature stop codon at amino acid position 620 of the LDLR protein and is thus predicted to result in a loss of function of the protein. The c.1860G>A change has not been reported in the ExAC database. Another nucleotide change (c.1859G>A) similarly resulting a non sense variant at the same amino acid position 620 (p.Trp620*) has also been reported in patients with hypercholesterolemia [PMID 11737238]. This c.1860G>A (p.Trp620*) variant is thus classified as pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000775248 SCV000909506 pathogenic Familial hypercholesterolemia 2023-09-01 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 13 in the LDLR type B repeat 6 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least two individuals affected with familial hypercholesterolemia (PMID: 20809525, 25846081, 28235710) and in one individual suspected to be affected with familial hypercholesterolemia (PMID: 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics RCV002411099 SCV002724100 pathogenic Cardiovascular phenotype 2022-01-24 criteria provided, single submitter clinical testing The p.W620* pathogenic mutation (also known as c.1860G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at nucleotide position 1860. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This variant has been reported in individuals with familial hypercholesterolemia (FH), segregating with disease in two families (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Fan LL et al. Appl Biochem Biotechnol, 2015 May;176:101-9; Xiang R et al. Atherosclerosis, 2017 03;258:84-88; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Fulgent Genetics, Fulgent Genetics RCV000237143 SCV002813234 pathogenic Hypercholesterolemia, familial, 1 2021-09-20 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV003480570 SCV004227681 pathogenic not provided 2022-09-26 criteria provided, single submitter clinical testing PP1, PM2_supporting, PVS1

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