Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000588772 | SCV000697213 | likely pathogenic | Familial hypercholesterolemia | 2017-05-19 | criteria provided, single submitter | clinical testing | Variant summary: The LDLR c.1867dupA (p.Ile623Asnfs) 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 pathogenic by our laboratory (e.g. c.2043C>A, p.Cys681X). One in silico tool predicts a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 121410 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. |
| Labcorp Genetics |
RCV000588772 | SCV001394640 | pathogenic | Familial hypercholesterolemia | 2022-02-05 | 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: 496021). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 33740630). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile623Asnfs*22) 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). |
| Ambry Genetics | RCV002413665 | SCV002721035 | pathogenic | Cardiovascular phenotype | 2021-12-15 | criteria provided, single submitter | clinical testing | The c.1867dupA pathogenic mutation, located in coding exon 13 of the LDLR gene, results from a duplication of A at nucleotide position 1867, causing a translational frameshift with a predicted alternate stop codon (p.I623Nfs*22). This alteration has been reported in association with familial hypercholesterolemia (FH) (Lee WJ et al. Genes (Basel), 2021 Sep;12; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). 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. |