Submissions for variant NM_000527.5(LDLR):c.1586+15C>T

gnomAD frequency: 0.00009  dbSNP: rs371716068

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581777	SCV000689763	likely benign	Hypercholesterolemia, familial, 1	2017-09-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000581777	SCV001281862	uncertain significance	Hypercholesterolemia, familial, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420868	SCV001623288	uncertain significance	not specified	2021-05-17	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1586+15C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 250196 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4e-05 vs 0.0013), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1586+15C>T in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002404583	SCV002708325	likely benign	Cardiovascular phenotype	2022-10-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV002529237	SCV003242990	likely benign	Familial hypercholesterolemia	2023-12-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003420018	SCV004113848	uncertain significance	LDLR-related condition	2022-10-26	criteria provided, single submitter	clinical testing	The LDLR c.1586+15C>T variant is predicted to interfere with splicing. This variant is predicted to alter splicing based on available splicing prediction programs (Alamut Visual v2.11). However, such computer prediction programs are imperfect. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11224453-C-T) and interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/491662/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.