Submissions for variant NM_000527.5(LDLR):c.1176C>T (p.Cys392=)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002328442	SCV002636917	likely benign	Cardiovascular phenotype	2019-09-03	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	RCV004005662	SCV004828018	uncertain significance	Hypercholesterolemia, familial, 1	2024-02-05	criteria provided, single submitter	clinical testing	This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 392 of the LDLR protein. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with LDLR-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005096570	SCV005747386	uncertain significance	Familial hypercholesterolemia	2024-03-12	criteria provided, single submitter	clinical testing	This sequence change affects codon 392 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. This variant is not present in population databases (gnomAD no frequency). 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: 1740791). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.