Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000237525 | SCV004022399 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-01-27 | reviewed by expert panel | curation | The NM_000527.5 (LDLR):c.1028G>A (p.Gly343Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PM5_Strong) 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: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.959, it is above 0.75. PP4: Variant meets PM2 and is identified in 1 index case who fulfil DLCN criteria for definite FH after alternative causes of high cholesterol were excluded, reported in ClinVar (SCV000583778.1) from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France. PM5_Strong: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met. PS4 not met: Variant meets PM2 and is reported in 1 index case and family fulfil FH criteria, reported from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France. PS3 not met: Functional data is not available. |
| LDLR- |
RCV000237525 | SCV000295151 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| U4M - |
RCV000237525 | SCV000583778 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002379060 | SCV002692605 | likely pathogenic | Cardiovascular phenotype | 2019-12-13 | criteria provided, single submitter | clinical testing | The p.G343D variant (also known as c.1028G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1028. The glycine at codon 343 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been detected in an individual with familial hypercholesterolemia (FH) (Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10). In addition, a different alteration located at the same position, p.G343S, has been reported in a number of individuals with familial hypercholesterolemia (Hobbs HH et al. Hum Mutat. 1992;1:445-66; Reshef A et al. Hum Genet. 1996;98:581-6; Thiart R et al. Mol Cell Probes. 2000;14:299-304; Fouchier SW et al. Hum Genet. 2001;109:602-15; Nissen H et al. Clin Genet. 1998;54:79-82; Mozas P et al. Hum Mutat. 2004;24:187; Bourbon M et al. Atherosclerosis. 2008;196:633-42; Bertolini S et al. Atherosclerosis. 2013;227:342-8; Huijgen R et al. Circ Cardiovasc Genet. 2011;4:413-7; Hooper AJ et al. Atherosclerosis. 2012;224:430-4), and reduced LDLR activity was revealed in some of those individuals (Hobbs HH et al. Hum Mutat. 1992;1:445-66; Thiart R et al. Mol Cell Probes. 2000;14:299-304). In addition, an in vitro study suggested that the p.G343S alteration would interfere with protein folding and thus surface expression (Boswell EJ et al. J Biol Chem. 2004;279:30611-21). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, the p.G343D variant is likely to be pathogenic. |