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

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238417	SCV000295293	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
GeneDx	RCV000255176	SCV000322301	likely pathogenic	not provided	2024-05-24	criteria provided, single submitter	clinical testing	Reported in individuals with a history of early-onset myocardial infarction (PMID: 30586733); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L380V); This variant is associated with the following publications: (PMID: 12124988, 25461735, 32041611, 32715071, 33740630, 25637381, 23669246, 21722902, 24507775, 23833242, 31447099, 34037665, 34040191, 33955087, 22683370, 21957200, 9104431, 30586733)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000586642	SCV000627015	pathogenic	Familial hypercholesterolemia	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 401 of the LDLR protein (p.Leu401Val). This variant is present in population databases (rs146200173, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9104431, 12124988, 21722902, 24507775, 25461735). This variant is also known as p.Leu380Val. ClinVar contains an entry for this variant (Variation ID: 161267). 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 with a positive predictive value of 95%. 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, 11810272, 15701167, 19843101). 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000238417	SCV000839994	likely pathogenic	Hypercholesterolemia, familial, 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 Diagnostics, LLC DBA Color Health	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.
Revvity Omics, Revvity	RCV000238417	SCV002022661	likely pathogenic	Hypercholesterolemia, familial, 1	2022-08-31	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000255176	SCV002502785	likely pathogenic	not provided	2021-11-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345455	SCV002650517	likely pathogenic	Cardiovascular phenotype	2021-07-16	criteria provided, single submitter	clinical testing	The p.L401V variant (also known as c.1201C>G), located in coding exon 9 of the LDLR gene, results from a C to G substitution at nucleotide position 1201. The leucine at codon 401 is replaced by valine, an amino acid with highly similar properties. This alteration, also referred to as L380V, has been reported in hypercholesterolemia and early onset myocardial infarction cohorts (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Lange LA et al. Am. J. Hum. Genet., 2014 Feb;94:233-45; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Khera AV et al. Circulation, 2019 03;139:1593-1602). This alteration was also described to segregate with the disease (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94). This variant has been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000238417	SCV003932178	likely pathogenic	Hypercholesterolemia, familial, 1	2023-03-06	criteria provided, single submitter	clinical testing	PS3_Moderate, PM2, PM5_Supporting, PP3
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255176	SCV004219938	likely pathogenic	not provided	2022-08-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0002 (5/24928 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431 (1997), 21722902 (2011), 25461735 (2015), 32715071(2020), 34037665 (2021) and 33740630 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
All of Us Research Program, National Institutes of Health	RCV000238417	SCV004820276	likely pathogenic	Hypercholesterolemia, familial, 1	2023-11-14	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	RCV002051660	SCV000190285	likely pathogenic	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
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	Hypercholesterolemia, familial, 1	2016-12-16	flagged submission	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	Hypercholesterolemia, familial, 1	2016-03-01	flagged submission	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238417	SCV000606356	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Iberoamerican FH Network	RCV000238417	SCV000748051	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	flagged submission	research
Natera, Inc.	RCV000586642	SCV002086413	pathogenic	Familial hypercholesterolemia	2020-01-22	no assertion criteria provided	clinical testing