Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory of Inherited Metabolic Diseases, |
RCV001249596 | SCV001244713 | pathogenic | Hypercholesterolemia, familial, 1 | 2020-01-05 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV001181835 | SCV001347074 | likely pathogenic | Familial hypercholesterolemia | 2023-11-30 | criteria provided, single submitter | clinical testing | This variant deletes four nucleotides, altering the canonical splice donor site in intron 6 of the LDLR gene. This variant is also known as c.940+1_c.940+4delGTGA using alternate nomenclature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in at least 7 heterozygous individuals affected with familial hypercholesterolemia (PMID: 32423031, 32770674, 33269076, 33418990; Color internal data). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in one individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 36901902). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
Invitae | RCV001181835 | SCV004376098 | pathogenic | Familial hypercholesterolemia | 2023-12-26 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 6 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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 32423031, 32770674, 33269076). ClinVar contains an entry for this variant (Variation ID: 869390). Variants that disrupt 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. For these reasons, this variant has been classified as Pathogenic. |