Submissions for variant NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu)

dbSNP: rs777188764

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000228158	SCV002506357	uncertain significance	Hypercholesterolemia, familial, 1	2022-03-30	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS4_supporting and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001848 (0.01848%) in European (Finnish) exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.937. PP4 - Variant meets PM2. Identified in 2 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with clinical Simon Broome score possible/definite, after alternative causes of high cholesterol were excluded. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome criteria (possible/definite).
LDLR-LOVD, British Heart Foundation	RCV000228158	SCV000295613	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000228158	SCV000540833	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000228158	SCV001422635	uncertain significance	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	curation	The p.Arg574Leu variant in LDLR has been reported in 1 Czech individual with Familial Hypercholesterolemia (PMID: 22698793), and has been identified in 0.01848% (4/21640) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs777188764). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 237867). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional likely pathogenic variants causing a different amino acid change at the same position, p.Arg574Cys and p.Arg574His, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 183123, 251996). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001339707	SCV001533471	uncertain significance	Familial hypercholesterolemia	2016-01-29	criteria provided, single submitter	clinical testing	In summary, this is a novel missense change with uncertain impact on protein function that has been reported in one patient. However, the clinical significance of this finding is still unknown. Therefore, it has been classified as a Variant of Uncertain Significance. 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 has been reported in an individual affected with hypercholesterolemia. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 22698793). This variant is present in population databases (rs777188764, ExAC 0.02%). This sequence change replaces arginine with leucine at codon 574 of the LDLR protein (p.Arg574Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine.
Color Diagnostics, LLC DBA Color Health	RCV001339707	SCV004358542	uncertain significance	Familial hypercholesterolemia	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg553Leu in the mature protein) replaces arginine with leucine at codon 574 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with familial hypercholesterolemia (PMID: 22698793; ClinVar SCV002506357.1). This variant has been identified in 4/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg574His and p.Arg574Cys, are considered to be disease-causing (ClinVar variation ID: 251996 and 183123), suggesting that arginine at this position is important for LDLR protein function. 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.
All of Us Research Program, National Institutes of Health	RCV000228158	SCV004822492	uncertain significance	Hypercholesterolemia, familial, 1	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg553Leu in the mature protein) replaces arginine with leucine at codon 574 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with familial hypercholesterolemia (PMID: 22698793; ClinVar SCV002506357.1). This variant has been identified in 4/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg574His and p.Arg574Cys, are considered to be disease-causing (ClinVar variation ID: 251996 and 183123), suggesting that arginine at this position is important for LDLR protein function. 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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000228158	SCV005374011	uncertain significance	Hypercholesterolemia, familial, 1	2024-09-22	criteria provided, single submitter	clinical testing