ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.4G>C (p.Gly2Arg)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237142 SCV002817168 uncertain significance Hypercholesterolemia, familial, 1 2022-04-29 reviewed by expert panel curation NM_000527.5(LDLR):c.4G>C (p.Gly2Arg)variant is classified as uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 and PP4 as defined by the ClinGen Familial NM_000527.5(LDLR):c.4G>C (p.Gly2Arg)variant is classified as uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 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 = 0.00016 (0.016%) in African exomes (gnomAD v2.1.1). PP4 - Variant meets PM2 and is identified in one index cases who fulfills SB criteria for FH (1 case from CGMC, UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière)).
LDLR-LOVD, British Heart Foundation RCV000237142 SCV000294410 likely benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237142 SCV000588479 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Color Diagnostics, LLC DBA Color Health RCV001182216 SCV001347575 likely benign Familial hypercholesterolemia 2019-02-01 criteria provided, single submitter clinical testing
Invitae RCV001182216 SCV002225591 uncertain significance Familial hypercholesterolemia 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2 of the LDLR protein (p.Gly2Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs5931, ExAC 0.02%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 11933210, 25461735). ClinVar contains an entry for this variant (Variation ID: 250971). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine 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.
Ambry Genetics RCV004020945 SCV005035888 uncertain significance Cardiovascular phenotype 2024-01-17 criteria provided, single submitter clinical testing The p.G2R variant (also known as c.4G>C), located in coding exon 1 of the LDLR gene, results from a G to C substitution at nucleotide position 4. The glycine at codon 2 is replaced by arginine, an amino acid with dissimilar properties. This variant and a different nucleotide substitution resulting in the same amino acid change (c.4G>A) have been detected in individuals from familial hypercholesterolemia cohorts (Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Salazar LA et al. Hum Mutat, 2002 Apr;19:462-3; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6). This amino acid position is not well conserved in available vertebrate species and arginine is the reference amino acid in many other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.

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