ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.2061dup (p.Asn688fs) (rs137853965)

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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 RCV000211582 SCV000295853 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Athena Diagnostics Inc RCV000058921 SCV000614006 pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844732 SCV000711401 pathogenic Familial hypercholesterolemia - homozygous 2017-05-12 criteria provided, single submitter clinical testing The p.Asn688Glnfsx29 variant in LDLR has been reported in 5 individuals with cli nical features of familial hypercholesterolemia (Graham et al. 2005; Humphries e t al. 2006, Hooper 2012, Vandrovcova 2013, Abul-Husn 2016) and has also been rep orted in ClinVar (Variation ID: 68103). It has been identified in 1/111648 Europ ean chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dbSNP rs137853965). This variant is predicted to cause a frameshif t, which alters the protein?s amino acid sequence beginning at position 688 and leads to a premature termination codon 29 amino acids downstream. This alteratio n is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. In summary, this variant meets criteria to be cla ssified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based on predicted impact to the protein, low frequency in controls and presence in multiple affected individuals.
Iberoamerican FH Network RCV000211582 SCV000748156 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000211582 SCV000752425 pathogenic Familial hypercholesterolemia 1 2017-12-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn688Glnfs*29) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs751228587, ExAC 0.002%). This variant has been reported in the literature in individuals affected with familial hypercholesterolemia (PMID: 27680772, 22883975, 16389549, 17539906, 16159606, 26046366). ClinVar contains an entry for this variant (Variation ID: 68103). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781503 SCV000919584 pathogenic Familial hypercholesterolemia 2017-11-27 criteria provided, single submitter clinical testing Variant summary: The LDLR c.2061dupC (p.Asn688GlnfsX29) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/246074 control chromosomes (in gnomAD) at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The variant was reported in several individuals affected by definite FH (Graham 2005, Humphries 2006, Martin 2016) In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
SNPedia RCV000058921 SCV000090442 not provided not provided no assertion provided not provided
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211582 SCV000268657 pathogenic Familial hypercholesterolemia 1 2008-08-25 no assertion criteria provided clinical testing

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