Submissions for variant NM_000527.5(LDLR):c.2388C>T (p.Ile796=)

gnomAD frequency: 0.00003  dbSNP: rs543852919

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001182970	SCV000544647	uncertain significance	Familial hypercholesterolemia	2021-07-13	criteria provided, single submitter	clinical testing	This sequence change affects codon 796 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs543852919, ExAC 0.009%). 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: 406165). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Robarts Research Institute, Western University	RCV000462919	SCV000782938	likely benign	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780381	SCV000917584	likely benign	not specified	2018-08-20	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2388C>T (p.Ile796Ile) 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. 5/5 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 277170 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2388C>T in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported in our internal database (LDLR c.1118_1121dupGTGG, p.Tyr375fsX7), providing supporting evidence for a benign role. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign" and "uncertain significance." Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001182970	SCV001348607	likely benign	Familial hypercholesterolemia	2018-12-05	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000780381	SCV002073470	likely benign	not specified	2022-01-14	criteria provided, single submitter	clinical testing	This synonymous variant has occurred in GnomAD with a total MAF of 0.0028% and with the highest MAF of 0.0054% in the European population. This position is 2 bp away from a canonical splicing site, and it is not conserved. In silico splicing algorithm predicted no impact on splicing, but no functional studies were performed to confirm this prediction. This variant NM_000527.5(LDLR):c.2388C>T (p.Ile796=) is present in the ClinVar database (ID: 406165). The variant has not occurred in the literature in association with the disease. Considering that the variant has a relatively high frequency in a subpopulation, it has been classified as Likely Benign.
Ambry Genetics	RCV002451092	SCV002738411	likely benign	Cardiovascular phenotype	2022-03-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
All of Us Research Program, National Institutes of Health	RCV000462919	SCV004820679	likely benign	Hypercholesterolemia, familial, 1	2023-12-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001182970	SCV001453901	likely benign	Familial hypercholesterolemia	2020-06-18	no assertion criteria provided	clinical testing