Submissions for variant NM_000527.5(LDLR):c.226G>T (p.Gly76Trp)

dbSNP: rs574337291

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237270	SCV004022425	uncertain significance	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.226G>T (p.Gly76Trp) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes BS3, PS4_Supporting, PM2, PP1_Moderate, 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: BS3: Level 1 assays: PMID 25741862: Heterologous cells (CHO), western blot and flow cytometry assays - result: 100% low-density lipoprotein particle receptor biosynthetic process; 90% low-density lipoprotein particle binding; 95% low-density lipoprotein particle clearance. ---- The whole cycle is above 90% of wild-type activity. So, BS3 is met. PS4_Supporting: Variant meets PM2 and is identified in 2 index cases (1 case with DLCN criteria of definite FH from U4M - Lille University & CHRU Lille and 1 case with Simon Broome criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). So, PS4_Supporting is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.898. It is above 0.75, so PP3 is met. PP1_Moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. So, PP1_Moderate is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH from different labs, after alternative causes of high cholesterol were excluded (see PS4 for details). So, PP4 is met.
LDLR-LOVD, British Heart Foundation	RCV000237270	SCV000294538	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237270	SCV000322879	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/100 normolipidemic individuals
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237270	SCV000503113	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation / mild phenotype / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237270	SCV000583641	likely pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182218	SCV001347577	likely benign	Familial hypercholesterolemia	2017-05-15	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001182218	SCV001423041	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	curation	The p.Gly76Trp variant in LDLR has been reported in at least 1 Portuguese individual with familial hypercholesterolemia (PMID: 17765246), and was absent from large population studies. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: rs574337291). In vitro functional studies provide some evidence that the p.Gly76Trp variant may not impact protein function (PMID: 25741862). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly76Trp variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, BS3_supporting (Richards 2015).
Ambry Genetics	RCV002446472	SCV002734015	uncertain significance	Cardiovascular phenotype	2021-12-23	criteria provided, single submitter	clinical testing	The p.G76W variant (also known as c.226G>T), located in coding exon 3 of the LDLR gene, results from a G to T substitution at nucleotide position 226. The glycine at codon 76 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration has been reported in a familial hypercholesterolemia (FH) cohort with limited clinical details and in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). An in vitro assay showed this alteration may not impact protein function (Benito-Vicente A et al. Genet Med, 2015 Dec;17:980-8). 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.
All of Us Research Program, National Institutes of Health	RCV000237270	SCV004820130	likely benign	Hypercholesterolemia, familial, 1	2023-02-24	criteria provided, single submitter	clinical testing
GeneDx	RCV004701333	SCV005201878	uncertain significance	not provided	2023-12-13	criteria provided, single submitter	clinical testing	Identified in a patient with familial hypercholesterolemia (FH) in published literature (PMID: 17765246); Not observed at significant frequency in large population cohorts (gnomAD); A published functional study suggests the p.(G76W) showed similar levels of expression and trafficking to cell surface compared to wildtype (PMID: 25741862); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G55W); This variant is associated with the following publications: (PMID: 32719484, 29261184, 29874871, 27821657, 22881376, 17765246, 25741862)