Submissions for variant NM_000527.5(LDLR):c.940G>A (p.Gly314Arg)

gnomAD frequency: 0.00004  dbSNP: rs72658858

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238096	SCV000295075	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455406	SCV000539508	uncertain significance	not specified	2017-01-24	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC with a MaxMAF of 0.006%. This region is not conserved and 4 mammals and 1 non-mammal have an Arg at this position. It is predicted benign by all predictive tools. It is present in ClinVar with 1 star and classified as VUS by the British Heart Foundation. It is present in 3 patients with FH.
Color Diagnostics, LLC DBA Color Health	RCV001185251	SCV001351424	uncertain significance	Familial hypercholesterolemia	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Gly293Arg in the mature protein) replaces glycine with arginine at codon 314 of the LDLR 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). A functional study has shown the mutant protein to show normal protein maturation and plasma membrane localization (Khalid Jawabri 2020, dissertation, United Arab Emirates University). This variant has been reported in several individuals affected with premature atherosclerosis and/or familial hypercholesterolemia in the literature (PMID: 17347910, 33794673). This variant has been identified in 13/282176 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.
Mendelics	RCV000455406	SCV002518180	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002372047	SCV002685014	uncertain significance	Cardiovascular phenotype	2022-01-07	criteria provided, single submitter	clinical testing	The p.G314R variant (also known as c.940G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 940. The glycine at codon 314 is replaced by arginine, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 6 and may have some effect on normal mRNA splicing. This variant (also described as legacy p.G293R) has been reported in hypercholesterolemia cohorts; however, clinical details were limited in many cases (Widhalm K et al. J Inherit Metab Dis, 2007 Apr;30:239-47; Durst R et al. Atherosclerosis, 2017 02;257:55-63; Futema M et al. Atherosclerosis, 2017 05;260:47-55; Turkyilmaz A et al. Metab Syndr Relat Disord, 2021 08;19:340-346). This variant was also reported in a myocardial infarction (MI) study, where it was detected in one non-MI participant; limited functional analyses suggested no significant impact (Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This amino acid position is not well conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000238096	SCV002792252	uncertain significance	Hypercholesterolemia, familial, 1	2021-10-26	criteria provided, single submitter	clinical testing
Invitae	RCV001185251	SCV003259699	uncertain significance	Familial hypercholesterolemia	2022-07-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 314 of the LDLR protein (p.Gly314Arg). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs72658858, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 17347910, 28104544, 28349888). This variant is also known as G293R. ClinVar contains an entry for this variant (Variation ID: 183102). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455406	SCV003934616	uncertain significance	not specified	2023-05-11	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.940G>A (p.Gly314Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. As the variant affects the last conserved nucleotide of exon 6 adjacent to the intron 6 splice donor site, 4/4 computational tools predict a slight weakening of the canonical 5'-splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 250802 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4.8e-05 vs 0.0013), allowing no conclusion about variant significance. c.940G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (example, Widhalm_2007, Durst_2017, Futema_2017, Rimbert_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28104544, 28349888, 35047021, 17347910). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161973	SCV000189548	not provided	not provided		no assertion provided	in vitro
Natera, Inc.	RCV001185251	SCV001460260	uncertain significance	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing