Submissions for variant NM_000527.5(LDLR):c.758G>A (p.Arg253Gln)

gnomAD frequency: 0.00001  dbSNP: rs139507589

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV002227241	SCV002506379	uncertain significance	Hypercholesterolemia, familial, 1	2022-04-22	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.758G>A (p.Arg253Gln) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.000096 (0.0096%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1). BP4 - REVEL = 0.44; score is below 0.5 threshold, splicing evaluation required. Functional data on splicing not available. Category B) - variant is exonic and at least 50bp upstream from the canonical donor site, and creates an AG. MES scores: de novo variant = 0; canonical acceptor site = 10.79; ratio = 0/10.79 = 0; this is below the threshold of 0.8 and therefore this variant is predicted to not affect splicing. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>C (p.Arg253Pro); however, both are VUS by these LDLR guidelines (PM5 not applicable).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001046025	SCV001209907	uncertain significance	Familial hypercholesterolemia	2024-04-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 253 of the LDLR protein (p.Arg253Gln). This variant is present in population databases (rs139507589, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 843407). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001046025	SCV001358760	uncertain significance	Familial hypercholesterolemia	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg232Gln in the mature protein) replaces arginine with glutamine at codon 253 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with familial hypercholesterolemia (doi:10.3390/jcm12031030). This variant has been identified in 4/282886 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.
Fulgent Genetics, Fulgent Genetics	RCV002227241	SCV002790530	uncertain significance	Hypercholesterolemia, familial, 1	2022-04-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV002227241	SCV004820207	uncertain significance	Hypercholesterolemia, familial, 1	2023-11-28	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Arg232Gln in the mature protein) is located in the LDLR type A repeat 6 of ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 4/277252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Ambry Genetics	RCV004031422	SCV005035889	uncertain significance	Cardiovascular phenotype	2023-10-24	criteria provided, single submitter	clinical testing	The p.R253Q variant (also known as c.758G>A), located in coding exon 5 of the LDLR gene, results from a G to A substitution at nucleotide position 758. The arginine at codon 253 is replaced by glutamine, an amino acid with highly similar properties. This variant co-occurred with a pathogenic mutation in the LDLR gene in an individual from a familial hypercholesterolemia cohort (Aparicio A et al. J Clin Med, 2023 Jan;12). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001046025	SCV001460258	uncertain significance	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing