Submissions for variant NM_000527.5(LDLR):c.917C>T (p.Ser306Leu) (rs11547917)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211683	SCV000295055	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute,Western University	RCV000211683	SCV000484690	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	RCV000211683	SCV000503253	likely pathogenic	Familial hypercholesterolemia 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	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Color Health, Inc	RCV001179372	SCV001344023	likely pathogenic	Familial hypercholesterolemia	2019-12-29	criteria provided, single submitter	clinical testing
Invitae	RCV001179372	SCV001399727	pathogenic	Familial hypercholesterolemia	2020-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine with leucine at codon 306 of the LDLR protein (p.Ser306Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with familial hypercholesterolemia (FH) and segregates with FH in families (PMID: 21642693, 16542394, 30795984, 11462246, 7489239, 1301956, 22390909, 21475731, 10532689, 15199436). This variant is also known as S285L and FH-Amsterdam in the literature. ClinVar contains an entry for this variant (Variation ID: 226337). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). For these reasons, this variant has been classified as Pathogenic. 5
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000211683	SCV001432672	pathogenic	Familial hypercholesterolemia 1	2019-06-05	criteria provided, single submitter	research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211683	SCV000268589	pathogenic	Familial hypercholesterolemia 1	2014-11-13	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211683	SCV000606268	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000211683	SCV000733816	pathogenic	Familial hypercholesterolemia 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