ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2140+1G>T

dbSNP: rs145787161
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation 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, LabCorp 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.

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