Submissions for variant NM_000527.5(LDLR):c.1618G>A (p.Ala540Thr)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001034632	SCV000285015	likely pathogenic	Familial hypercholesterolemia	2019-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with threonine at codon 540 of the LDLR protein (p.Ala540Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (no rsID, ExAC 0.01%). This variant has been reported in the literature in multiple individuals affected with familial hypercholesterolemia (PMID: 9544745, 11196104, 15200491, 15241806, 18718593, 21376320, 23375686, 24075752, 25461735) and hyperlipidemia (PMID: 19007590). This variant is also known as A519T in the literature. ClinVar contains an entry for this variant (Variation ID: 226363). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function that has been reported in multiple familial hypercholesterolemia individuals. For these reasons, it has been classified as Likely Pathogenic.
LDLR-LOVD, British Heart Foundation	RCV000211624	SCV000295541	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211624	SCV000322966	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles
Robarts Research Institute,Western University	RCV000211624	SCV000484729	likely pathogenic	Familial hypercholesterolemia 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000211624	SCV000503376	likely pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 (2 homozygotes), family members 1 (1 homozygote) with co-segregation) / previously described in association with FH/Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation	RCV000211624	SCV000540827	likely pathogenic	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211624	SCV000583853	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211624	SCV000588598	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211624	SCV000607618	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000996756	SCV001151664	likely pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV001034632	SCV001339063	pathogenic	Familial hypercholesterolemia	2020-03-30	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1618G>A (p.Ala540Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251472 control chromosomes. c.1618G>A has been reported in the literature in multiple individuals affected with Hypercholesterolemia (Sun_1998, Merino-Ibarra_2007, Bertolini_2013, Martin_2016). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000211624	SCV001432660	pathogenic	Familial hypercholesterolemia 1	2019-03-10	criteria provided, single submitter	research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211624	SCV000268625	pathogenic	Familial hypercholesterolemia 1	2011-04-08	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211624	SCV000606468	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research