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	likely pathogenic	not provided	2021-08-19	criteria provided, single submitter	clinical testing	Reported in 2 cases and 1 control in a study of individuals with a history of early-onset myocardial infarction (Khera et al., 2019); Reported in ClinVar (ClinVar Variant ID# 161267; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33740630, 32715071, 32041611, 26582918, 30586733, 9104431, 25461735, 12124988, 31447099, 23833242, 24507775, 21722902, 23669246, 25637381)
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	2020-08-05	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071) and segregated with disease in multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
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