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

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000003884	SCV005375280	pathogenic	Hypercholesterolemia, familial, 1	2023-01-27	reviewed by expert panel	curation	The NM_000527.5(LDLR): c.1567G>A (p.Val523Met) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, PM3, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003266 (0.003%) in East Asian (gnomAD v2.1.1). PP3: REVEL = 0.917. PS3_Moderate: Functional studies: PMID 1301956 (Hobbs et al., 1992), Level 2 assay using homozygous patients' fibroblasts, 125I-LDL assays - 15-30% LDLR activity (but all cycle was tested) // PMID 9974426 (Bertolini et al., 1999), Level 2 assay using homozygous patient fibroblast, 125I-LDL assays - 25% LDLR activity, (mention of testing LDL binding, internalization, and degradation) // PMID 21865347 (Romano et al., 2011), Level 3 assays using heterozygous patients' Epstein-Barr virus transformed lymphocytes and FACS assays - 30-40% LDLR activity. // PMID 25647241 (Thormaehlen et al., 2015), functional studies using HeLa cells and alternative microscopy assay showed that the LDLR activity is decreased compared to WT and was considered as "disruptive" ------ Overall, functional studies (PMID 1301956, 9974426, 21865347) show an activity below 70% of wild-type, consistent with damaging effect and PS3 is met. PS4, PP4: Variant meets PM2 and is identified in at least 22 unrelated cases, 2 fulfilling Simon-Broome criteria (GeneDx) and 20 with DLCN score >=6 (Service de Biochimie et de Biologie Moléculaire, France; Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy; Robarts Research Institute, Canada). PP1_Strong: variant segregates with FH phenotype in 14 informative meioses in 8 families from different labs (Service de Biochimie et de Biologie Moléculaire, France; Laboratory of Genetics and Molecular Cardiology, Brazil; Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy): 11 affected family members have the variant and 3 non-affected family members do not have the variant. PM3: 1 case reported from Service de Biochimie et de Biologie Moléculaire, France (homozygous and LDL-cholesterol 12 mmol/L at 4 years old).
LDLR-LOVD, British Heart Foundation	RCV000003884	SCV000295499	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000003884	SCV000484683	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003884	SCV000583848	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003884	SCV000588586	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000003884	SCV000607607	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000587718	SCV000909173	pathogenic	Familial hypercholesterolemia	2019-09-30	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Val502Met in the mature protein and as FH Kuwait, FH Bari-2) replaces valine with methionine at codon 523 in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant causes LDLR recycling defect (PMID: 2088165) and results in a significantly reduced LDLR activity in cells from homozygous individuals (PMID: 9974426). This variant has been reported in over 15 European individuals affected with familial hypercholesterolemia (PMID: 7616128, 12436241, 15241806, 20045108, 26892515), including several homozygous and compound heterozygous individuals (PMID: 9974426, 30795984). This variant has been identified in 3/251336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000587718	SCV000940009	pathogenic	Familial hypercholesterolemia	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 523 of the LDLR protein (p.Val523Met). This variant is present in population databases (rs28942080, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2088165, 14974088, 15256764, 21310417, 21865347, 22294733, 23375686, 25463123, 27765764). This variant is also known as V502M. ClinVar contains an entry for this variant (Variation ID: 3696). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LDLR 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. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825622	SCV000966974	pathogenic	Homozygous familial hypercholesterolemia	2020-05-28	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). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 3696) and has been identified in 0.003% (1/30782) of South Asian and 0.002% (2/111654) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the heterozygous p.Val523Met variant may impact protein function (Romano 2011). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PM2, PS3_Supporting, PM3_Strong.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000587718	SCV001422746	likely pathogenic	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	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).
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000003884	SCV001430013	pathogenic	Hypercholesterolemia, familial, 1	2018-03-16	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000003884	SCV001433508	pathogenic	Hypercholesterolemia, familial, 1	2019-04-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003884	SCV001440422	likely pathogenic	Hypercholesterolemia, familial, 1	2019-01-01	criteria provided, single submitter	clinical testing
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000003884	SCV001653640	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing	Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.
Revvity Omics, Revvity	RCV000003884	SCV002017132	pathogenic	Hypercholesterolemia, familial, 1	2022-04-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399309	SCV002708769	pathogenic	Cardiovascular phenotype	2024-05-06	criteria provided, single submitter	clinical testing	The c.1567G>A (p.V523M) alteration is located in coding exon 10 of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1567, causing the valine (V) at amino acid position 523 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (3/251336) total alleles studied. The highest observed frequency was 0.003% (1/30616) of South Asian alleles. This alteration has been reported in the homozygous and heterozygous states in multiple individuals with familial hypercholesterolemia from various ethnic groups (Hobbs, 1992; Lombardi, 1995; Bertolini, 1999; Amsellem, 2002; Leren, 2004; Mozas, 2004; Dušková, 2011; Mollaki, 2014; Sharifi, 2016; Luirink, 2019). This amino acid position is well conserved in available vertebrate species. Internal structural analysis indicates this alteration to be structurally disruptive (Lo Surdo, 2011). In addition, a number of studies have reported this alteration to attenuate LDLR activity (Hobbs, 1992; Bertolini, 1999; Romano, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000003884	SCV002822895	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000161992	SCV005198655	likely pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing
OMIM	RCV000003884	SCV000024049	pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2013-01-23	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003884	SCV000606453	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000161992	SCV001923962	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000161992	SCV001962947	pathogenic	not provided		no assertion criteria provided	clinical testing