Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000237339 | SCV000295893 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000985766 | SCV001134259 | pathogenic | not provided | 2022-08-15 | criteria provided, single submitter | clinical testing | The LDLR c.2140+1G>T variant disrupts a canonical splice-donor site and interferes with normal LDLR mRNA splicing. This variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (FH) (PMIDs: 29292049 (2018), 23375686 (2013), 10441197 (1999), 28932795 (2015), 34037665 (2021), 35339733 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001260306 | SCV001437229 | pathogenic | Familial hypercholesterolemia | 2020-09-08 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.2140+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250282 control chromosomes. c.2140+1G>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (examples- Peeters_1999, Bertolini_2013, Tada_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Invitae | RCV001260306 | SCV001586206 | pathogenic | Familial hypercholesterolemia | 2023-08-27 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 252235). This variant is also known as IVS14+1G>T. Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 10441197, 11313767, 23375686, 28932795). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 14 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV002429175 | SCV002729254 | pathogenic | Cardiovascular phenotype | 2020-09-09 | criteria provided, single submitter | clinical testing | The c.2140+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 14 of the LDLR gene. This alteration (also referred to by legacy nomenclature, IVS14+1G>T) has been reported in individuals with familial hypercholesterolemia (Peeters AV et al. Mol. Cell. Probes, 1999 Aug;13:257-60; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |