Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002050668 | SCV002112000 | uncertain significance | Familial hypercholesterolemia | 2021-01-25 | criteria provided, single submitter | clinical testing | This variant disrupts the c.c.313+6 nucleotide in the LDLR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 17765246, 19411563). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. 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 may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 3 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site of the intron. |
| Ambry Genetics | RCV002324221 | SCV002607714 | likely pathogenic | Cardiovascular phenotype | 2022-11-02 | criteria provided, single submitter | clinical testing | The c.313+6T>G intronic variant results from a T to G substitution 6 nucleotides after coding exon 3 in the LDLR gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Other nearby alterations impacting the same donor site (c.313+6T>C and c.313+5G>A) have been shown to have a similar impact on RNA splicing (Liguori R et al. Hum. Mutat., 2001 May;17:433; Bourbon M et al. J Med Genet, 2009 May;46:352-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |