Submissions for variant NM_000527.5(LDLR):c.1201C>G (p.Leu401Val)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238417	SCV000295293	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
GeneDx	RCV000255176	SCV000322301	pathogenic	not provided	2016-08-25	criteria provided, single submitter	clinical testing	The L401V variant in the LDLR gene has been reported previously in the heterozygous state in multiple individuals with familial hypercholesterolemia (Leren et al., 1997; Vaca et al., 2011; Jannes et al., 2015). Note that Leren et al. described L401V using alternate nomenclature L380V (1997). The L401V variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L401V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue, L401H, was previously reported, using alternate nomenclature L308H and referred to as FH-Pori, in four unrelated individuals of Finnish descent with heterozygous familial hypercholesterolemia (Koivisto et al., 1995), supporting the functional importance of this region of the protein. Therefore, we interpret L401V as a known pathogenic variant.
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000238417	SCV000503313	uncertain significance	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 compound heterozygous on LDL Apheresis /FH-Norvege / Software predictions: Conflicting
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000238417	SCV000588564	uncertain significance	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000586642	SCV000627015	pathogenic	Familial hypercholesterolemia	2020-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with valine at codon 401 of the LDLR protein (p.Leu401Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs146200173, ExAC 0.02%). This variant has been reported in individuals affected with hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 24507775). It is also known as p.Leu380Val in the literature. This variant has been reported in individuals in the Universal Mutation Database (PMID: 12124988) and has an entry in ClinVar (Variation ID: 161267). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant disrupts the p.Leu401 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7573037, 19843101, 15701167, 11810272). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America	RCV000586642	SCV000697189	pathogenic	Familial hypercholesterolemia	2016-04-28	criteria provided, single submitter	clinical testing	Variant summary: The c.1201C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant is found in 2/119858 control chromosomes at a frequency of 0.0000167, which does not exceed maximal expected frequency of a pathogenic allele (0.0012508) to exclude pathogenicity. The variant was reported in several FH patients and one study reported the variant to co-segregate with hypercholesterolemia (Leren_JIM_19970) indicating pathogenicity. In addition, a clinical laboratory and a reputable database classify this variant as Likely pathogenic / Disease causing. Taken together, this variant was classified as Pathogenic.
Iberoamerican FH Network	RCV000238417	SCV000748051	uncertain significance	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000238417	SCV000839994	likely pathogenic	Familial hypercholesterolemia 1	2018-05-11	criteria provided, single submitter	clinical testing	The c.1201C>G (p.Leu401Val) variant in the LDLR gene has been observed in multiple individuals with familial hypercholesteromeia (PMID: 9104431, 21722902, 25461735). In addition, a missense variant at the same residue, p.Leu401His, has been previously reported in other affected individuals (PMID: 7573037, 11810272,15701167). Therefore, this variant in the LDLR gene is classified as likely pathogenic.
Color Health, Inc	RCV000586642	SCV001347900	likely pathogenic	Familial hypercholesterolemia	2020-01-21	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148572	SCV000190285	likely pathogenic	Hypercholesterolaemia	2014-06-01	no assertion criteria provided	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000238417	SCV000606356	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research