ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1911delC (p.Asp638Metfs) (rs867272973)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Robarts Research Institute,Western University RCV000408859 SCV000484805 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000516597 SCV000614005 pathogenic not provided 2016-08-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586615 SCV000697215 likely pathogenic Familial hypercholesterolemia 2017-02-06 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1911delC (p.Asp638Metfs) 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. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (e.g. p.Cys681X, p.Trp813X). Mutation taster predicts a damaging outcome for this variant. This variant is absent in 121406 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000586615 SCV000836496 pathogenic Familial hypercholesterolemia 2020-03-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp638Metfs*27) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LDLR-related disease. ClinVar contains an entry for this variant (Variation ID: 369869). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000408859 SCV000839999 likely pathogenic Familial hypercholesterolemia 1 2018-04-25 criteria provided, single submitter clinical testing This c.1910delC (p.Asp638Metfs*27) variant in the LDLR gene has not been reported previously nor observed in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.1910delC (p.Asp638Metfs*27) variant in the LDLR gene is classified as likely pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825596 SCV000966938 likely pathogenic Homozygous familial hypercholesterolemia 2018-05-04 criteria provided, single submitter clinical testing The p.Asp638fs variant in LDLR has not been previously reported in the literatur e, but has been reported in ClinVar (Variation ID# 369869). This variant has bee n identified in 1/8254 European American chromosomes by the NHLBI Exome Sequenci ng Project (; dbSNP rs1057516131). Please note that for diseases with clinical variability, reduced penetrance, or recessive in heritance, pathogenic variants may be present at a low frequency in the general population. This variant is predicted to cause a frameshift, which alters the pr otein?s amino acid sequence beginning at position 638 and leads to a premature t ermination codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDL R gene is an established disease mechanism in familial hypercholesterolemia. In summary, although additional studies are required to fully establish its clinica l significance, the p.Asp638fs variant is likely pathogenic. ACMG/AMP Criteria a pplied: PVS1, PM2.
Color Health, Inc RCV000586615 SCV001356941 pathogenic Familial hypercholesterolemia 2021-02-03 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 13 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is also known as c.1910delC in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 28964736, 32770674; Color internal data). 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000408859 SCV000606555 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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