Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237806 | SCV000295365 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Labcorp Genetics |
RCV001368837 | SCV001565251 | uncertain significance | Familial hypercholesterolemia | 2020-02-15 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine with histidine at codon 442 of the LDLR protein (p.Tyr442His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia or premature atherosclerosis (PMID: 17347910, 22220933). This variant is also known as Y421H in the literature. ClinVar contains an entry for this variant (Variation ID: 251786). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Tyr442 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 15576851, 11857755), which suggests that this may be a clinically significant amino acid residue. |
| Ambry Genetics | RCV002379062 | SCV002689070 | likely pathogenic | Cardiovascular phenotype | 2021-07-07 | criteria provided, single submitter | clinical testing | The p.Y442H variant (also known as c.1324T>C), located in coding exon 9 of the LDLR gene, results from a T to C substitution at nucleotide position 1324. The tyrosine at codon 442 is replaced by histidine, an amino acid with similar properties, and is located in the YWTD motif of the LDLR type B repeat region. This variant, also referred to as p.Y421H, has been detected in individuals with definite or suspected familial hypercholesterolemia (FH); however, details were limited (Widhalm K et al. J Inherit Metab Dis, 2007 Apr;30:239-47; Ambry internal data). This variant has also been detected in a sudden death victim with atherosclerosis, ventricular dilation, and myocyte degeneration in the setting of a history of reported anabolic steroid abuse (Larsen MK et al. J Forensic Sci, 2012 May;57:658-62; Larsen MK et al. Forensic Sci Int, 2012 Jun;219:33-8). Based on internal structural analysis, this variant is predicted to be structurally disruptive to the LDLR type B repeat (Jeon H et al. Nat Struct Biol. 2001 Jun;8(6):499-504; Lo Surdo P et al. EMBO Rep. 2011 Dec;12(12):1300-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is 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. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237806 | SCV000606393 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |