Submissions for variant NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys) (rs879254781)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237189	SCV000295202	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	RCV000237189	SCV000503294	pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 12 , family members = 11 with co-segregation / FH-Paris-7 / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237189	SCV000583785	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Iberoamerican FH Network	RCV000237189	SCV000748095	uncertain significance	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Color	RCV000775054	SCV000909154	likely pathogenic	Familial hypercholesterolemia	2019-03-22	criteria provided, single submitter	clinical testing
Invitae	RCV000775054	SCV000963893	likely pathogenic	Familial hypercholesterolemia	2018-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 357 of the LDLR protein (p.Glu357Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with familial hypercholesterolemia or with clinical features of this condition (PMID: 1301956, 28502510, 10735632, 15199436, Invitae). This variant is also known as E336K in the literature. ClinVar contains an entry for this variant (Variation ID: 251649). 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.Glu357 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000237189	SCV000606318	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Broad Institute Rare Disease Group,Broad Institute	RCV000775054	SCV001422598	likely pathogenic	Familial hypercholesterolemia	2020-01-22	no assertion criteria provided	curation	The p.Glu357Lys variant in LDLR has been reported in at least 11 individuals with familial hypercholesterolemia, segregated with disease in 6 affected relatives from 1 family (PMID: 15199436), and was absent from large population studies. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 251649). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1_moderate, PP3, PS4_supporting (Richards 2015).