Submissions for variant NM_000527.5(LDLR):c.917C>T (p.Ser306Leu)

dbSNP: rs11547917

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211683	SCV000295055	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211683	SCV000484690	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	RCV000211683	SCV000503253	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation / FH-Amsterdam, 2 to 5% LDLR Activity / Software predictions: Conflicting
Fundacion Hipercolesterolemia Familiar	RCV000211683	SCV000607523	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001179372	SCV001344023	likely pathogenic	Familial hypercholesterolemia	2019-12-29	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ser285Leu in the mature protein and as FH Amsterdam) is located in the LDLR type A repeat 7 of the ligand binding 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). Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental functional study has shown that this variant causes significant decrease in LDLR activity (PMID: 1301956). This variant has been reported in more than 400 individuals affected with familial hypercholesterolemia (PMID: 10532689, 1301956, 15199436, 16542394, 20506408, 21475731, 27919364, 30270091) and is considered a founder mutation in the Netherlands (PMID: 21475731). 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	RCV001179372	SCV001399727	pathogenic	Familial hypercholesterolemia	2023-04-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 226337). This variant is also known as S285L and FH-Amsterdam. This missense change has been observed in individuals with FH and familial hypercholesterolemia (FH) (PMID: 1301956, 7489239, 10532689, 11462246, 15199436, 16542394, 21475731, 21642693, 22390909, 30795984). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 306 of the LDLR protein (p.Ser306Leu).
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211683	SCV001432672	pathogenic	Hypercholesterolemia, familial, 1	2019-06-05	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000786353	SCV001961772	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000211683	SCV002017119	pathogenic	Hypercholesterolemia, familial, 1	2021-07-22	criteria provided, single submitter	clinical testing
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000211683	SCV002320841	pathogenic	Hypercholesterolemia, familial, 1	2022-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002372215	SCV002685747	pathogenic	Cardiovascular phenotype	2019-03-19	criteria provided, single submitter	clinical testing	The p.S306L pathogenic mutation (also known as c.917C>T), located in coding exon 6 of the LDLR gene, results from a C to T substitution at nucleotide position 917. The serine at codon 306 is replaced by leucine, an amino acid with dissimilar properties. This alteration, has been reported in many individuals with familial hypercholesterolemia and has been reported as one of the most prevalent mutations in the Netherlands (Jensen HK et al. Atherosclerosis. 1999;146(2):337-44; Fouchier SW et al. Hum Genet. 2001;109(6):602-15; Huijgen R et al. Hum Mutat. 2010;31(6):752-60; Kusters DM et al. Neth Heart J. 2011;19(4):175-182; van der Graaf A et al. Circulation. 2011;123(11):1167-73; Huijgen R et al. Eur Heart J. 2012;33(18):2325-30). In addition, this mutation was reported in an individual with 2-5% LDL receptor activity, although this individual was thought to be a compound heterozygote for another unspecified alteration. In the same study, this mutation was characterized as functional class 2B (Hobbs HH et al. Hum Mutat. 1992;1(6):445-66). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000786353	SCV002774350	pathogenic	not provided	2021-08-27	criteria provided, single submitter	clinical testing	This variant has been reported in individuals and families with familial hypercholesterolemia in the published literature (PMIDs: 21475731 (2011), 11845603 (2001), 11462246 (2001), and 7489239 (1995)). This variant has been described as a founder mutation from the Netherlands (PMID: 21475731 (2011)). Functional studies of patient cells with this variant showed a substantial decrease in LDLR activity (PMID: 1301956 (1992)). Based on the available information, this variant is classified as pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211683	SCV000268589	pathogenic	Hypercholesterolemia, familial, 1	2014-11-13	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211683	SCV000606268	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000211683	SCV000733816	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786353	SCV000925139	pathogenic	not provided	2016-09-06	no assertion criteria provided	provider interpretation	The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified (see report below): p.Ser306Leu (c.917C>T) in the LDLR gene (NM_000527.4) The lab classifies this variant as a pathogenic mutation. Given sufficient case data we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been reported in at least 10 unrelated cases of familial hypercholesterolemia (not including this patient's family). There is strong case data. This variant has been identified in many individuals with familial hypercholesterolemia and one of the most prevalent variants in the Netherlands and has been known as the FH Amsterdam allele in publication (aka p.Ser285Leu). Hobbs, et al 1992 reported this variant in their cohort of Dutch patients. The individual had homozygous FH phenotype but the other variant could no be identified at the time of the study. Schuster, et al 1996 reports a family in which five individuals had the Ser306Leu variant in a heterozygous state and one individual who had p.Ser306Leu in a homozygous state. They had phenotypes of heterozygous and homozygous FH respectively. This study reported on a German cohort. Jensen, et al reported this variant in their Danish cohort in 1999. No individual details were provided other than the patient having the clinical diagnosis of FH. The Rotterdam study (Oosterveer, et al, 2015) identified Ser306Leu in 19 individuals (many unrelated individuals, but clinical information is not proved). Clinvar reports this variant in one individual that was tested at the PathWest Lab Medicine, no additional details are given. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.965). The serine at codon 306 is conserved across species, as are neighboring amino acids. There is no variation at codon 306 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 9, 2016). The average coverage at that site in ExAC is 80x.
Clinical Genetics, Academic Medical Center	RCV000786353	SCV001920541	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745282	SCV005351180	pathogenic	LDLR-related disorder	2024-05-03	no assertion criteria provided	clinical testing	The LDLR c.917C>T variant is predicted to result in the amino acid substitution p.Ser306Leu. This variant (also denoted as p.Ser285Leu in the literature) has been reported as causative for familial hypercholesterolemia (see for examples Hobbs et al. 1992. PubMed ID: 1301956; Jensen et al. 1999. PubMed ID: 10532689; Leren et al. 2004. PubMed ID: 15199436). This variant has also been reported in the compound heterozygous state in pediatric cases of familial hypercholesterolemia (Luirink et al. 2018. PubMed ID: 30795984). This variant has not been documented in a large population database, indicating this variant is rare. However, many of the reported cases are individuals from the Netherlands and it is thought that this variant may be a founder variant within this population (Kusters et al. 2011. PubMed ID: 21475731). For this reason, this variant is sometimes referred to as "FH Amsterdam" in the literature. Given all the evidence, we interpret c.917C>T (p.Ser306Leu) as pathogenic.