Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000161988 | SCV000234649 | pathogenic | not provided | 2016-06-22 | criteria provided, single submitter | clinical testing | The D472Y c.1414 GAC>TAC variant in the LDLR gene has been published previously as a disease-causing variant in association with hypercholesterolemia (Campagna et al., 2008; Bertolini et al., 2013). Based on the ACMG recommendations, D472Y is interpreted as a known pathogenic sequence change. |
LDLR- |
RCV000237883 | SCV000295416 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000237883 | SCV000503344 | likely benign | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting |
Molecular Genetics Laboratory, |
RCV000237883 | SCV000540817 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000844749 | SCV000731720 | likely pathogenic | Homozygous familial hypercholesterolemia | 2017-08-03 | criteria provided, single submitter | clinical testing | The p.Asp472Tyr variant in LDLR (also described as p.Asp451Tyr in the literature ) has been reported in 10 individuals with familial hypercholesterolemia (FH) an d 12 individuals who had a myocardial infarction, and segregated with disease in 3 affected relatives from 2 families (Abul-Husn 2016, Vohnout 2016, Thormaehlen 2015, Tichy 2012, Bertolini 2013, Do 2015, Campagna 2008). This variant has als o been reported by other clinical laboratories in ClinVar (Variation ID 183116) and has been identified in 5/30778 of South Asian chromosomes and 8/126504 Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org/; dbSNP 730882102). This frequency is low enough to be consistent w ith the frequency of FH in the general population. Computational prediction tool s and conservation analysis do not provide strong support for or against an impa ct to the protein and in vitro functional assays were unclear in their overall i mpact (Thormaehlen 2015). In summary, although additional studies are required t o fully establish its clinical significance, the p.Asp472Tyr variant is likely p athogenic. ACMG/AMP Criteria applied (Richards 2015): PS4, PM2, PP1. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000161988 | SCV000888161 | likely pathogenic | not provided | 2018-05-04 | criteria provided, single submitter | clinical testing | |
Color Health, |
RCV000775068 | SCV000909169 | likely pathogenic | Familial hypercholesterolemia | 2020-03-11 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000775068 | SCV001227232 | uncertain significance | Familial hypercholesterolemia | 2019-12-13 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid with tyrosine at codon 472 of the LDLR protein (p.Asp472Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs730882102, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed to segregate with hypercholesterolemia in families (PMID: 17196209, 27542166). This variant is also known as p.D451Y and p.D304Y in the literature. ClinVar contains an entry for this variant (Variation ID: 183116). This variant has been reported to affect LDLR protein function (PMID: 25647241). 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. |
Dept. |
RCV000161988 | SCV000189563 | not provided | not provided | no assertion provided | in vitro | ||
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237883 | SCV000606418 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research |