ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.12G>A (p.Trp4Ter)

dbSNP: rs756039188
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000791411 SCV000285010 pathogenic Familial hypercholesterolemia 2023-12-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp4*) 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 (rs756039188, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7903864, 16314194, 20428891, 21376320, 21868016). ClinVar contains an entry for this variant (Variation ID: 237860). For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000227275 SCV000294414 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000227275 SCV000583622 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing ACMG Guidelines: Pathogenic (i)
Fundacion Hipercolesterolemia Familiar RCV000227275 SCV000607403 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000227275 SCV000748035 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000227275 SCV001422788 pathogenic Hypercholesterolemia, familial, 1 2020-01-22 criteria provided, single submitter curation The p.Trp4Ter (sometimes called p.Trp-18Ter) variant in LDLR has been reported in 53 individuals (including including 48 Spanish, 3 Chinese, and 2 Mexican individuals) with Familial Hypercholesterolemia, segregated with disease in 3 affected relatives from 1 family (PMID: 7903864, 20428891, 21868016, 1301956, 16314194), and has been identified in 0.002897% (1/34516) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs756039188). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar (Variation ID: 237860). This nonsense variant leads to a premature termination codon at position 4, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in Familial Hypercholesterolemia. One pathogenic variant with the same amino acid change as this variant has been reported in association with Familial Hypercholesterolemia in ClinVar, supporting that this variant may be pathogenic (Variation ID: 250973). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PS1, PS4, PP1 (Richards 2015).
Revvity Omics, Revvity RCV000227275 SCV002017124 pathogenic Hypercholesterolemia, familial, 1 2019-07-29 criteria provided, single submitter clinical testing

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