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

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211624	SCV002568031	pathogenic	Hypercholesterolemia, familial, 1	2022-08-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1618G>A (p.Ala540Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PP1_Strong, PM2, PM3, PP3, PP4, PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS4 - variant meets PM2 and was identified in: - at least 1 index case with DLCN at least 8 (TC =700mg/dl) from Ambry Genetics, USA; - 14 unrelated index cases, all with DLCN >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - at least 5 unrelated index cases (3 with Simon Broome definite FH, 2 with Simon Broome possible FH) from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; - 2 unrelated index cases who fulfill SB criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal; - 4 unrelated index cases, all with DLCN >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia; - 2 unrelated index cases, all with Dutch lipid clinic network >=6 from Robarts Research Institute, Canada; - at least 1 index case with DLCN>=6 from PMID 19318025 (Alonso et al., 2009), Spain; - at least 1 index case with SB criteria for FH from PMID 21376320 Chiou et al., 2011), Taiwan, --- 30 cases, so PS4 is met PP1_strong - variant segregates with the FH phenotype in 39 informative meiosis from at least 14 families: - 20 informative meiosis from 7 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo: 16 relatives with the variant have LDL-C >75th percentile, and 4 relatives without the variant have LDL-C <50th percentile; - 1 informative meiosis from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 1 relative positive for variant had LDL-C >75th percentile; - 8 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): F1 with 2 relatives positive for variant and having LDL-C >75th percentile, and 2 relatives negative for variant and having LDL-C <50th percentile, F2: 1 relative who was positive for the variant and had LDL-C >75th percentile, F3: 2 relatives who were positive for variant with LDL-C >75th percentile, and 1 relative who was negative for the variant with LDL-C <50th percentile; - 2 informative meiosis from 2 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 1 relative positive for variant with LDL-C >75th percentile in each family; - 8 informative meiosis (unknown how many families) from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA): 5 relatives positive for variant with LDL-C >75th percentile, and 3 relatives were negative for variant with LDL-C <50th percentile. --- 39 segregations, so PP1_Strong is met PM2 - PopMax MAF = 0.00006533 (0.007%) in South Asian exomes (gnomAD v2.1.1). It is below than 0.02%, so PM2 is met. PM3 - variant meets PM2 and was identified in: - 1 index case homozygous for the variant with TC = 700mg/dl at 7 years old from Ambry Genetics. ---> individual is homozygous for variant and has an homozygous phenotype, so PM3 is met. - 2 unrelated index cases, both homozygous for the variant, with LDL-C 352mg/dL under statin treatment (352/0.7 = 503mg/dl) and LDL-C=409mg/dl under statin treatment (409/0.7 = 584mg/dl), respectively, both from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) ---> individuals are homozygous for variant and have an homozygous phenotype, so PM3 is met. PP3 - REVEL = 0.888. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in at least 30 unrelated index cases who fulfill clinical FH criteria (see PS4 for details), so PP4 is met. PS3_supporting - Level 3 FS: Sun et al., 1997 (PMID 9409298) - Htz patients' fibroblasts, immunoblot and 125I-LDL assays - results: 40-50% LDLR activity, cell surface LDLR 40-50% LDLR. --- Activity is below 85%, so PS3_Supporting is met.
Invitae	RCV001034632	SCV000285015	pathogenic	Familial hypercholesterolemia	2023-07-10	criteria provided, single submitter	clinical testing	This variant is also known as A519T. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 540 of the LDLR protein (p.Ala540Thr). This variant is present in population databases (rs769370816, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia and hyperlipidemia (PMID: 9544745, 11196104, 15200491, 15241806, 18718593, 19007590, 21376320, 23375686, 24075752, 25461735). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 226363). 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. For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation	RCV000211624	SCV000295541	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211624	SCV000322966	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles
Robarts Research Institute, Western University	RCV000211624	SCV000484729	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	RCV000211624	SCV000503376	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211624	SCV000583853	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211624	SCV000588598	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211624	SCV000607618	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000996756	SCV001151664	likely pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001034632	SCV001339063	pathogenic	Familial hypercholesterolemia	2022-03-14	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 (example, Sun_1998, Merino-Ibarra_2007, Bertolini_2013, Martin_2016). These data indicate that the variant is very likely to be associated with disease. Twelve 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	Hypercholesterolemia, familial, 1	2019-03-10	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449699	SCV001652954	pathogenic	Homozygous familial hypercholesterolemia	2020-11-15	criteria provided, single submitter	clinical testing	The p.Ala540Thr variant in LDLR (also described as p.Ala519Thr in the literature) has been reported in >17 individuals with familial hypercholesterolemia (FH) or hyperlipidemia, including in one homozygote and in 1 compound heterozygote with another pathogenic variant and segregated with disease in at least 9 affected relatives from 4 families (Sun 1997 PMID: 9409298, Weiss 2000 PMID: 11196104, Mozas 2004 PMID: 15241806, Dedoussis 2004 PMID: 15200491, Leren 2004 PMID: 15199436, Civeira 2008 PMID: 19007590, Miyake 2009 PMID: 18718593, Chiou 2011 PMID: 21376320, Faiz 2013 PMID: 24075752, Bertolini 2013 PMID: 23375686, Jannes 2015 PMID: 25461735, Martin 2016 PMID: 27680772, Kellogg 2018 (https://doi.org/10.1101/425975)). It has also been reported by other clinical laboratories in ClinVar (Variation ID:226363) and has been identified in 0.007% (2/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies support an impact on protein function (Sun 1997 PMID: 9409298) and computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting.
DASA	RCV000211624	SCV002073775	likely pathogenic	Hypercholesterolemia, familial, 1	2022-02-05	criteria provided, single submitter	clinical testing	The c.1618G>A;p.(Ala540Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 226363; PMID: 9544745; 11196104; 15200491; 15241806; 18718593; 21376320; 23375686; 24075752; 25461735; 19007590) - PS4. The variant is present at low allele frequencies population databases (rs769370816 – gnomAD 0.00007953%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 15241806) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Ambry Genetics	RCV002399780	SCV002708009	pathogenic	Cardiovascular phenotype	2022-01-11	criteria provided, single submitter	clinical testing	The p.A540T variant (also known as c.1618G>A), located in coding exon 11 of the LDLR gene, results from a G to A substitution at nucleotide position 1618. The alanine at codon 540 is replaced by threonine, an amino acid with similar properties. This alteration, also known as p.A519T, has been detected in a number of individuals with familial hypercholesterolemia (FH) from various ethnic groups (Weiss N et al. J Inherit Metab Dis. 2000;23:778-90; Leren TP et al. Semin Vasc Med. 2004;4:75-85; Dedoussis GV et al. Eur J Clin Invest. 2004;34:402-9; Civeira F et al. J Am Coll Cardiol. 2008;52:1546-53; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445; Hori M et al. Atherosclerosis, 2019 10;289:101-108; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). Several homozygous FH cases have been reported, including individuals homozygous for p.A540T, as well as compound heterozygotes with other LDLR alterations (Bertolini S et al. Atherosclerosis. 2013;227:342-8; Rocha VZ et al. J Am Coll Cardiol, 2013 May;61:2193; Santos RD. Atheroscler Suppl, 2014 Sep;15:19-25; Jannes CE et al. Atherosclerosis. 2015;238:101-7; S&aacute;nchez-Hern&aacute;ndez RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510). In one study, cultured cells from a patient heterozygous for this alteration exhibited reduced LDLR activity and protein expression compared with cells from a control individual (Sun XM et al. Arterioscler Thromb Vasc. Biol. 1997;17:3092-101). Based on internal structural analysis, p.A540T is moderately destabilizing to the local structure (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
New York Genome Center	RCV000211624	SCV002764277	likely pathogenic	Hypercholesterolemia, familial, 1	2021-04-20	criteria provided, single submitter	clinical testing	The c.1618G>A (p.Ala540Thr) variant identified in the LDLR gene substitutes a well conserved Alanine for Threonine at amino acid 540/861 (exon 11/18). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.001) and Pathogenic (REVEL; score:0.888) to the function of the canonical transcript. This variant is reported as Pathogenic and Likely Pathogenic in ClinVar (VarID:226363), and has been reported in multiple affected individuals in the literature [PMID:11196104, 15241806, 18718593, 21376320, others], includingin some families in which it segregates with disease. Given its presence in multiple affected individuals in the literature, absence in population databases, and in silico prediction of deleterious effect on protein function, the c.1618G>A (p.Ala540Thr) variant identified in the LDLR gene is reported as Likely Pathogenic.
Revvity Omics, Revvity	RCV000211624	SCV003827684	pathogenic	Hypercholesterolemia, familial, 1	2022-10-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000996756	SCV004219954	pathogenic	not provided	2023-01-05	criteria provided, single submitter	clinical testing	The LDLR c.1618G>A (p.Ala540Thr) variant (also known as A519T) has been reported in multiple individuals with familial hypercholesterolemia (FH) (PMIDs: 32331935 (2020), 23375686 (2013), 18718593 (2009), 19007590 (2008), 15241806 (2004), 15200491 (2004), 15199436 (2004), 11196104 (2000)). It has also been reported in cases of homozygous and compound heterozygous FH (PMIDs: 32977124 (2020), 24561735 (2015)). A functional study indicated the variant caused reduced LDLR activity (PMID: 9409298 (1997)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. The frequency of this variant in the general population, 0.000008 (2/251472 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211624	SCV000268625	pathogenic	Hypercholesterolemia, familial, 1	2011-04-08	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211624	SCV000606468	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
deCODE genetics, Amgen	RCV000211624	SCV004022248	likely pathogenic	Hypercholesterolemia, familial, 1	2023-07-21	no assertion criteria provided	research	The variant NM_000527.5:c.1618G>A (chr19:11116125) in LDLR was detected in 11 heterozygotes out of 58K WGS Icelanders (MAF= 0,009%). Following imputation in a set of 166K Icelanders (22 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 1.39, P= 3.27e-06) and Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 1.16, P= 1.02e-04). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PS4, PM1, PP3, PP5_Strong) this variant classifies as likely pathogenic.