Submissions for variant NM_000527.5(LDLR):c.710G>A (p.Arg237His)

gnomAD frequency: 0.00005  dbSNP: rs148171426

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000417334	SCV000503228	likely benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Color Diagnostics, LLC DBA Color Health	RCV000775604	SCV000909968	uncertain significance	Familial hypercholesterolemia	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg216His in the mature protein) replaces arginine with histidine at codon 237 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental cell-based high-throughput LDLR activity assay has shown that this variant may be non-disruptive for LDLR function (PMID: 25647241). To our knowledge, this variant has not been reported in individuals affected with LDLR-related disorders in the literature, but it has been reported in several healthy control individuals (PMID: 25487149). This variant has been identified in 13/282882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775604	SCV003521574	likely benign	Familial hypercholesterolemia	2024-12-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477911	SCV004219996	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with high LDL cholesterol (PMID: 24507775 (2014)). The frequency of this variant in the general population, 0.000085 (3/35438 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000417334	SCV004820203	uncertain significance	Hypercholesterolemia, familial, 1	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg216His in the mature protein) replaces arginine with histidine at codon 237 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental cell-based high-throughput LDLR activity assay has shown that this variant may be non-disruptive for LDLR function (PMID: 25647241). To our knowledge, this variant has not been reported in individuals affected with LDLR-related disorders in the literature, but it has been reported in several healthy control individuals (PMID: 25487149). This variant has been identified in 13/282882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.