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

Total submissions: 12

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	2021-04-07	criteria provided, single submitter	clinical testing	The p.Asp472Tyr variant in LDLR (also described as p.Asp451Tyr in the literature) has been reported in >15 individuals with familial hypercholesterolemia (FH) and 12 individuals who had a myocardial infarction, and segregated with disease in 3 affected relatives from 2 families (Abul-Husn 2016 PMID: 28008010, Vohnout 2016 PMID: 27542166, Thormaehlen 2015 PMID: 25647241, Tichy 2012 PMID: 22698793, Bertolini 2013 PMID: 23375686, Do 2015 PMID: 25487149, Campagna 2008 PMID: 17196209, ClinVar submission IDs: SCV000503344.1, SCV000540817.1). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 183116) and has been identified in 0.02% (5/30612) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, and in vitro functional assays were unclear in their overall impact (Thormaehlen 2015 PMID: 25647241). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PM2_Supporting, 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, Inc	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000775068	SCV001623423	likely pathogenic	Familial hypercholesterolemia	2021-05-10	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1414G>T (p.Asp472Tyr) results in a non-conservative amino acid change located in the class B repeat domain (IPR000033) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251206 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (5.6e-05 vs 0.0013), allowing no conclusion about variant significance. c.1414G>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example: Bertolini_2013, Futema_2021, Hou_2020) where it is also known to segregate with the disease in at least two families (Vohnoout_2016, Campagna_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports that the variant affects LDLR protein function (Thormaehlen_2015). Eight ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic (n=6), uncertain significance (n=1) or likely benign (n=1). There are other missense variants reported in Human Gene Mutation Database (HGMD) affecting the same and/or nearby codons (example: p.S470C, p.D472N, p.I473N) associated Hypercholesterolaemia suggesting this region may be clinically significant. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000237883	SCV001653634	likely pathogenic	Familial hypercholesterolemia 1	2021-05-24	criteria provided, single submitter	clinical testing
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