Submissions for variant NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln)

gnomAD frequency: 0.00007  dbSNP: rs200142970

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000210245	SCV002568110	uncertain significance	Hypercholesterolemia, familial, 1	2022-05-30	reviewed by expert panel	curation	NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, 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 = 0.0001602 (0.01602%) in African/African American exomes+genomes (gnomAD v2.1.1). PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases (1 case published in PMID: 16250003 (Fouchier et al., 2005), Netherlands; 1 case published in PMID: 16159606 (Graham et al., 2005), United Kingdom). PP4 - Variant meets PM2. PMID: 16159606 - 1 case who fulfills Simon-Broome criteria for FH.
CSER _CC_NCGL, University of Washington	RCV002051679	SCV000190308	uncertain significance	Hypercholesterolemia	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000210245	SCV000266313	uncertain significance	Hypercholesterolemia, familial, 1	2015-08-31	criteria provided, single submitter	research	MAF =<0.3%, LDL-C >=160 mg/dL
LDLR-LOVD, British Heart Foundation	RCV000210245	SCV000295926	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815637	SCV000956098	uncertain significance	Familial hypercholesterolemia	2024-09-28	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 751 of the LDLR protein (p.Arg751Gln). This variant is present in population databases (rs200142970, gnomAD 0.02%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 16159606, 16250003, 33955087). ClinVar contains an entry for this variant (Variation ID: 161286). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LDLR protein function with a negative predictive value of 95%. 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	RCV000815637	SCV001344869	uncertain significance	Familial hypercholesterolemia	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 751 of the LDLR protein. This variant is also known as p.Arg730Gln in the mature protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with familial hypercholesterolemia (PMID: 16159606, 16250003, 28145427, 33955087). This variant has also been identified in 22/282676 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.
GeneDx	RCV000996761	SCV001785178	uncertain significance	not provided	2019-06-06	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28145427, 16159606, 16250003, 25637381, 18325082)
Ambry Genetics	RCV002444608	SCV002735235	likely benign	Cardiovascular phenotype	2022-05-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV000210245	SCV004818517	uncertain significance	Hypercholesterolemia, familial, 1	2024-09-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 751 of the LDLR protein. This variant is also known as p.Arg730Gln in the mature protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with familial hypercholesterolemia (PMID: 16159606, 16250003, 28145427, 33955087). This variant has also been identified in 22/282676 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000210245	SCV000606620	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000815637	SCV001461330	uncertain significance	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing