ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1448G>A (p.Trp483Ter)

dbSNP: rs875989921
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211662 SCV000295438 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000211662 SCV000607601 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001049393 SCV001213439 pathogenic Familial hypercholesterolemia 2023-04-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 226356). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7903864, 18247305). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp483*) 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).
Color Diagnostics, LLC DBA Color Health RCV001049393 SCV001341142 pathogenic Familial hypercholesterolemia 2021-01-04 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 10 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 over 25 individuals affected with familial hypercholesterolemia (PMID: 23375686, 25846081, 27170061, 28235710, 28502495, 29233637). 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. Based on available evidence, this variant is classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia RCV000211662 SCV001432635 pathogenic Hypercholesterolemia, familial, 1 2019-03-10 criteria provided, single submitter research
Ambry Genetics RCV004020584 SCV003968367 pathogenic Cardiovascular phenotype 2023-05-12 criteria provided, single submitter clinical testing The c.1448G>A (p.W483*) alteration, located in exon 10 (coding exon 10) of the LDLR gene, consists of a G to A substitution at nucleotide position 1448. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 483. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation, often reported in the Chinese population (also referred to as W462* or Trp462Stop), has been detected in the heterozygous, homozygous and compound heterozygous states in many individual with heterozygous or homozygous familial hypercholesterolemia (FH), and has shown segregation with FH in families (Sun, 1994; Schmidt, 2000; Cheng, 2008; Jiang, 2016; Marco-Benedí, 2022). Functional studies have shown this variant to adversely impact protein function (Cheng, 2008; Wang, 2009; Jiang, 2016). Based on the available evidence, this alteration is classified as pathogenic.
First Hospital of Lanzhou University, Lanzhou University RCV000211662 SCV004801756 pathogenic Hypercholesterolemia, familial, 1 2024-02-23 criteria provided, single submitter clinical testing A 38-year-old female proband carried compound heterozygous variations(c.292G>A,c.1864G> A and c.1448G> A, according to the ACMG guidelines they were separately classified as Uncertain significance, Likely pathogenic and pathogenic).The proband presented with a xanthoma, corneal aneurysm, and coronary artery disease. The patient's serum cholesterol concentration remained greater than 13 mmol/L after receiving intensive statin, evolocumab and Inclisiran therapy.We speculate that the hepatocytes of the proband indicate the almostly absence of LDLR. The proband's mother, sister, and son all carried the c.292G>A,c.1864G> A variant. The proband's father, both brothers and daughter carried the c.1448G> A variant. All of her relatives showed hypercholesterolemia, but no atherosclerosis, xanthoma, or corneal aneurysm in the other relatives except the proband. Pedigree co-segregation evidence suggests that the three variants may be pathogenic variants in this familial hypercholesterolemic family.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211662 SCV000268617 pathogenic Hypercholesterolemia, familial, 1 2013-09-17 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000211662 SCV000606430 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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