ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1911del (p.Asp638fs)

dbSNP: rs867272973
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Total submissions: 12
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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 Hypercholesterolemia, familial, 1 criteria provided, single submitter clinical testing
Athena Diagnostics 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 pathogenic Familial hypercholesterolemia 2023-02-20 criteria provided, single submitter clinical testing Variant summary: LDLR c.1911delC (p.Asp638MetfsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251488 control chromosomes (gnomAD). c.1911delC has been reported in the literature in multiple individuals affected with (familial) hypercholesterolemia (e.g. Defesche_2017, Zouk_2019, Rieck_2020, Sturm_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000586615 SCV000836496 pathogenic Familial hypercholesterolemia 2023-11-28 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. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 369869). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000408859 SCV000839999 likely pathogenic Hypercholesterolemia, familial, 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, Mass General Brigham Personalized Medicine RCV000825596 SCV000966938 pathogenic Homozygous familial hypercholesterolemia 2021-06-16 criteria provided, single submitter clinical testing The p.Asp638MetfsX27 variant in LDLR has been reported in at least 3 individuals with familial hypercholesterolemia (FH; Defesche 2017 PMID: 28964736, Zouk 2019 PMID: 31447099, Rieck 2020 PMID: 32770674, LMM data, ClinVar Variation ID 369869). It has also been identified in 1/8254 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) but was absent in gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 638 and leads to a premature termination codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting.
Color Diagnostics, LLC DBA Color Health 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000516597 SCV002103278 pathogenic not provided 2021-11-17 criteria provided, single submitter clinical testing PM2, PS4_moderate, PVS1
Ambry Genetics RCV002411270 SCV002719972 pathogenic Cardiovascular phenotype 2022-05-04 criteria provided, single submitter clinical testing The c.1911delC pathogenic mutation, located in coding exon 13 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 1911, causing a translational frameshift with a predicted alternate stop codon (p.D638Mfs*27). This alteration has been detected in a hypercholesterolemia cohort (Defesche JC. J Clin Lipidol. 2017;11(6):1338-1346.e7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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 RCV000408859 SCV002775786 pathogenic Hypercholesterolemia, familial, 1 2021-10-17 criteria provided, single submitter clinical testing
GeneDx RCV000516597 SCV003933342 pathogenic not provided 2023-07-20 criteria provided, single submitter clinical testing Reported in association with FH in published literature (Defesche et al., 2017; Rieck et al., 2020; Sturm et al., 2021) and in a patient with FH referred for genetic testing at GeneDx; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26582918, 32770674, 31447099, Schoen2014[abstract], 32719484, 28964736, 34037665)
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000408859 SCV000606555 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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