Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002041241 | SCV002309243 | likely pathogenic | Familial hypercholesterolemia | 2022-04-26 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 436 of the LDLR protein (p.Val436Glu). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val436 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9184256, 21722902, 30270359), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (Invitae). It has also been observed to segregate with disease in related individuals. |
| Ambry Genetics | RCV002386926 | SCV002693562 | likely pathogenic | Cardiovascular phenotype | 2019-05-09 | criteria provided, single submitter | clinical testing | The p.V436E variant (also known as c.1307T>A), located in coding exon 9 of the LDLR gene, results from a T to A substitution at nucleotide position 1307. The valine at codon 436 is replaced by glutamic acid, an amino acid with dissimilar properties. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). An alternate amino acid substitution at this codon, p.V436A, has been reported in individuals with familial hypercholesterolemia (FH), shown to co-segregate with disease, and reported to result in deficient LDL-receptor expression (Lombardi P et al. Clin. Genet., 1997 Apr;51:286-7; Selberg O et al. J Appl Res., 2003;3:495-504; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |