Submissions for variant NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr) (rs730882102)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	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-LOVD, British Heart Foundation	RCV000237883	SCV000295416	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	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,Centre for Cardiovascular Surgery and Transplantation	RCV000237883	SCV000540817	likely pathogenic	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized 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	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. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161988	SCV000189563	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000237883	SCV000606418	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research