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

dbSNP: rs879254781

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237189	SCV004022414	likely pathogenic	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS4_moderate, PP3 and PP4) 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: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PM3 - Variant meets PM2 and is identified in 2 compound heterozygous cases (1 case in PMID: 30179711 (Lock et al., 2018) with LDL = 23.89 mmol/L and also LDLR c.2043C>A - Pathogenic by these guidelines; 1 case in PMID: 19026292 (Kolansky et al., 2008) with LDL = 16.29 mmol/L and also LDLR c.1775G>A - Pathogenic by these guidelines). PS4_moderate - Variant meets PM2 and is identified in 8 unrelated index cases (3 cases with DLCN criteria>=6 and 1 case with Simon-Broome criteria of possible FH from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 unrelated case fulfilling internationally accepted criteria (Defesche 2000; Goldstein et al. 1995) for definite heterozygous FH published in PMID: 11810272 (Fouchier et al., 2001), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 21382890 (van der Graaf et al., 2011), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 10735632 (Lombardi et al., 2000), The Netherlands; 1 unrelated case with DLCN criteria>=6 published in PMID: 28502510 (Bañares et al., 2017), Argentina). PP3 - REVEL = 0.976. PP4 - Variant meets PM2 and is identified in at least one index case who fufills clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded.
LDLR-LOVD, British Heart Foundation	RCV000237189	SCV000295202	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Iberoamerican FH Network	RCV000237189	SCV000748095	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000775054	SCV000909154	likely pathogenic	Familial hypercholesterolemia	2019-03-22	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Glu336Lys in the mature protein and as FH Paris-7) replaces glutamic acid with lysine at codon 357 in the EGF-like repeat B of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional study has shown that this variant may cause defect in protein transport or recycling (PMID: 1301956). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11810272, 1301956, 20506408, 21382890, 23833242). This variant has been reported in compound heterozygosity with c.2034C>A (p.Cys681*) in a young child affected with familial hypercholesterolemia and prominent corneal arcus (PMID: 30179711). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775054	SCV000963893	pathogenic	Familial hypercholesterolemia	2023-01-16	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 251649). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 357 of the LDLR protein (p.Glu357Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 10735632, 15199436, 28502510, 30179711; Invitae). This variant is also known as E336K. 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. This variant disrupts the p.Glu357 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000775054	SCV001422598	likely pathogenic	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	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).
Ambry Genetics	RCV002411084	SCV002719859	likely pathogenic	Cardiovascular phenotype	2022-01-24	criteria provided, single submitter	clinical testing	The p.E357K variant (also known as c.1069G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1069. The glutamic acid at codon 357 is replaced by lysine, an amino acid with similar properties. This variant was detected in a pediatric clinical homozygous familial hypercholesterolemia (FH) case with a second LDLR mutation in trans, as well as in his heterozygous affected father (Lock JH et al. J AAPOS, 2018 Dec;22:467-468). This variant (also described as legacy p.E336K and FH Paris-7) has been reported in numerous FH cohorts, although clinical details were limited in most cases (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Kolansky DM et al. Am. J. Cardiol., 2008 Dec;102:1438-43; Huijgen R et al. Hum. Mutat., 2010 Jun;31:752-60). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000237189	SCV004175969	likely pathogenic	Hypercholesterolemia, familial, 1	2023-11-16	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PM3,PM2_SUP,PP3,PP4
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017551	SCV004848233	pathogenic	Homozygous familial hypercholesterolemia	2019-06-07	criteria provided, single submitter	clinical testing	The p.Glu357Lys variant in LDLR, also known as p.Glu336Lys or FH Paris 7, has been reported in the heterozygous state at least 10 probands with hypercholestrolemia (Hobbs 1992, Lombardi 2000, Huijgen 2010, Fouchier 2014, Banares 2017) and segregated with disease in at least 4 affected family members (Kusters 2013). In addition, this variant was identified in the compound heterozygous state with another pathogenic variant in a child with a severe presentation. It was inherited from his mother who had borderline high cholesterol (Lock 2018). This variant has been identified in multiple individuals in a large cohort from the Netherlands with mutation carriers (n=27) having mean LDL of 6.51 mmol/L compared to family members who were not carriers of the variant (n=100) with mean LDL of 3.37 mmol/L (Fouchier 2014). This variant is absent from large population studies but has been reported in ClinVar (Variation ID # 251649). Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PM2, PM3, PP1, PP3.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001699265	SCV005198651	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001699265	SCV005370114	likely pathogenic	not provided	2024-03-28	criteria provided, single submitter	clinical testing	Observed with a pathogenic variant on the opposite allele (in trans) in two patients with a clinical diagnosis of HoFH (PMID: 19026292, 30179711); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as FH Paris-7 and p.(E336K); This variant is associated with the following publications: (PMID: 22390909, 1301956, 28502510, 30179711, 32719484, 33740630, 34037665, 33087929, 33955087, 35177841, 19026292, 11810272, 21382890, 10735632)
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237189	SCV000606318	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV001699265	SCV001917359	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001699265	SCV001962763	pathogenic	not provided		no assertion criteria provided	clinical testing