Submissions for variant NM_000527.5(LDLR):c.898A>G (p.Arg300Gly)

gnomAD frequency: 0.00001  dbSNP: rs767618089

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237850	SCV002817154	likely pathogenic	Hypercholesterolemia, familial, 1	2022-10-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.898A>G (p.Arg300Gly) variant is classified as likely Pathogenic variant for Familial Hypercholesterolemia by applying evidence code PM2, PS3 and PS4 supporting 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_Met : PopMax MAF = 0.00003 in European (Non-Finnish) exomes (gnomAD v2.1.1) PS3_Met : Level 1 assay: Study of the whole LDLR cycle in Heterologous cells (CHO-ldlA7 cells), WB+FACS+CLSM. LDLR expression was not statistically different as compared to control. Conversely, LDL binding (<60%) and uptake (<60%) were significantly decreased (P<0.001). Interestingly, although the variant affects LDL binding and uptake, do not affect VLDL uptake. This reveals that the conformational change occurring in the module does not propagate to the whole ligand binding domain. (from PMID:25545329)
LDLR-LOVD, British Heart Foundation	RCV000237850	SCV000295037	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237850	SCV000583755	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000237850	SCV000607518	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000237850	SCV002499073	pathogenic	Hypercholesterolemia, familial, 1	2022-02-21	criteria provided, single submitter	clinical testing	PS3, PS4_Moderate, PM1, PM2
3billion	RCV000237850	SCV002572850	pathogenic	Hypercholesterolemia, familial, 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25545329). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.56; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with LDLR -related disorder (ClinVar ID: VCV000251510 / PMID: 19318025). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25545329 , 28965616 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV003456385	SCV004185155	likely pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	LDLR: PM1, PM2, PS4:Moderate, PS3:Supporting
All of Us Research Program, National Institutes of Health	RCV000237850	SCV004841081	likely pathogenic	Hypercholesterolemia, familial, 1	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg279Gly in the mature protein) replaces arginine with glycine at codon 300 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). Functional studies in LDLR-deficient cells indicated that this variant resulted in normal LDLR expression, but caused partial impairment (~50-60%) in LDL binding and uptake compared to wild-type LDLR (PMID: 25545329). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 19446849, 23375686, 27578128, 27784735, 28965616, 30293936, 32757650; ClinVar SCV002572850.1; SCV000583755.1). This variant has been identified in 3/251386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV004020954	SCV005035841	uncertain significance	Cardiovascular phenotype	2023-11-17	criteria provided, single submitter	clinical testing	The p.R300G variant (also known as c.898A>G), located in coding exon 6 of the LDLR gene, results from an A to G substitution at nucleotide position 898. The arginine at codon 300 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH) (Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). Additionally, an in vitro assay showed this alteration may reduce protein function (Etxebarria A et al. Atherosclerosis, 2015 Feb;238:304-12). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003456385	SCV005201883	likely pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies of the whole LDLR cycle performed in heterologous cells demonstrate a damaging effect through decreased LDL binding (55%) and uptake (60%) compared to wild type (PMID: 25545329); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.R279G; This variant is associated with the following publications: (PMID: 23375686, 32977124, 19318025, 30710474, 19446849, 28965616, 25545329)