ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1202T>A (p.Leu401His)

dbSNP: rs121908038
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003933 SCV000295294 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Invitae RCV001220262 SCV001392242 pathogenic Familial hypercholesterolemia 2019-11-07 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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: 9104431, 21722902, 25461735, 24507775). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 and their clinical significance is uncertain. This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 7573037, 19843101, 15701167, 11810272). This variant is also known as p.Leu380His or FH-Pori in the literature. ClinVar contains an entry for this variant (Variation ID: 3735). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with histidine at codon 401 of the LDLR protein (p.Leu401His). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and histidine.
Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine RCV001220262 SCV001482462 uncertain significance Familial hypercholesterolemia criteria provided, single submitter research
Ambry Genetics RCV002345226 SCV002652764 pathogenic Cardiovascular phenotype 2022-03-25 criteria provided, single submitter clinical testing The p.L401H pathogenic mutation (also known as c.1202T>A), located in coding exon 9 of the LDLR gene, results from a T to A substitution at nucleotide position 1202. The leucine at codon 401 is replaced by histidine, an amino acid with similar properties. This alteration (also referred to as L380H and FH-Pori), has been detected in several unrelated individuals with familial hypercholesterolemia (FH) and in FH cohorts (Koivisto UM et al. Am. J. Hum. Genet. 1995;57:789-97; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Zakharova FM et al. BMC Med. Genet. 2005;6:6; Alver M et al. Genet Med. 2019 05;21(5):1173-1180; Meshkov A et al. Genes (Basel). 2021 01;12(1)). Another alteration at the same codon, p.L401V (c.1201C>G), has also been reported in association with FH (Leren TP et al. J. Intern. Med. 1997;241:185-94). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Department of Human Genetics, Hannover Medical School RCV000003933 SCV005051693 likely pathogenic Hypercholesterolemia, familial, 1 2024-06-12 criteria provided, single submitter clinical testing
OMIM RCV000003933 SCV000024098 pathogenic Hypercholesterolemia, familial, 1 1995-10-01 no assertion criteria provided literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000003933 SCV000606357 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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