Submissions for variant NM_000527.5(LDLR):c.1567G>A (p.Val523Met)

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003884	SCV000295499	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute,Western University	RCV000003884	SCV000484683	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	RCV000003884	SCV000503365	likely pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 , family members = 4 with co-segregation / FH-Koweit-Bari,15 to 30% LDLR Activity/Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation	RCV000003884	SCV000540825	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	RCV000003884	SCV000583848	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003884	SCV000588586	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000003884	SCV000607607	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Integrated Genetics/Laboratory Corporation of America	RCV000587718	SCV000697201	pathogenic	Familial hypercholesterolemia	2016-08-09	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1567G>A (p.Val523Met) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120764 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Iberoamerican FH Network	RCV000003884	SCV000748098	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Color Health, Inc	RCV000587718	SCV000909173	pathogenic	Familial hypercholesterolemia	2019-09-30	criteria provided, single submitter	clinical testing
Invitae	RCV000587718	SCV000940009	likely pathogenic	Familial hypercholesterolemia	2019-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine with methionine at codon 523 of the LDLR protein (p.Val523Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs28942080, ExAC 0.006%). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 2088165, 23375686, 21865347, 22294733, 14974088, 15256764, 21310417, 25463123, 27765764). This variant is also known as V502M in the literature. ClinVar contains an entry for this variant (Variation ID: 3696). This variant has been reported not to substantially affect LDLR protein function (PMID: 25647241). This variant disrupts the p.Val523 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20809525), 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000825622	SCV000966974	pathogenic	Homozygous familial hypercholesterolemia	2019-03-26	criteria provided, single submitter	clinical testing	The p.Val523Met variant in LDLR (also referred as p.Val502Met, FH Kuwait, and FH Bari-2) has been reported in >100 heterozygous individuals with hypercholesterolemia as well as in at least 3 homozygous individuals and 3 compound heterozygous individuals with homozygous familial hypercholesterolemia (Hobbs 1990, Tichy 2012, Bertolini 2013, Wang 2016, Sánchez-Hernández 2016, Pirillo 2017). This variant also segregated with homozygous familial hypercholesterolemia in 1 homozygous relative (Bertolini 2013). In vitro functional studies provide some evidence that the heterozygous p.Val523Met variant may impact protein function (Romano 2011). It has been reported in ClinVar (Variation ID: 3696) and has also been identified in 1/30782 South Asian and 2/111654 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28942080). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon proband count, absence from controls, and functional studies. The ACMG/AMP Criteria applied: PS4, PM2, PS3_Supporting, PM3_Strong.
Institute of Human Genetics, Klinikum rechts der Isar	RCV000003884	SCV001430013	pathogenic	Familial hypercholesterolemia 1	2018-03-16	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000003884	SCV001433508	pathogenic	Familial hypercholesterolemia 1	2019-04-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003884	SCV001440422	likely pathogenic	Familial hypercholesterolemia 1	2019-01-01	criteria provided, single submitter	clinical testing
OMIM	RCV000003884	SCV000024049	pathogenic	Familial hypercholesterolemia 1	2014-08-27	no assertion criteria provided	literature only
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161992	SCV000189567	not provided	not provided		no assertion provided	in vitro
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003884	SCV000268622	pathogenic	Familial hypercholesterolemia 1	2013-01-23	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000003884	SCV000606453	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Broad Institute Rare Disease Group, Broad Institute	RCV000587718	SCV001422746	likely pathogenic	Familial hypercholesterolemia	2020-01-22	no assertion criteria provided	curation	The p.Val523Met variant in LDLR has been reported in at least 15 individuals with familial hypercholesterolemia (PMID: 15241806, 25463123, 15199436, 9974426, 7616128, 2088165, 21310417, 26892515, 12436241), and has been identified in 0.003% (1/30616) of South Asian chromosomes and 0.002% (2/113644) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28942080). This variant has also been reported in ClinVar as pathogenic or likely pathogenic (Variation ID: 3696). In vitro functional studies provide some evidence that the p.Val523Met variant may slightly impact protein function (PMID: 25647241, 21865347). However, these types of assays may not accurately represent biological function. 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: PS4, PP3, PS3_supporting (Richards 2015).