ClinVar Genomic variation as it relates to human health

subjects mutated among 2600 FH index cases screened = 6 , family members = 2 with co-segregation / Functional test, FH-Naples-2, 2% LDLR Activity, Other mutations at same codon / Software predictions: Damaging

The p.Gly565Val variant in LDLR (also described as p.Gly544Val in the literature) has been reported in the heterozygous state in at least 5 individuals and in the homozygous state in 1 individual with familial hypercholesterolemia (FH) and segregated with disease in 2 affected relatives from at least one family (ClinVar: SCV000503387.1 and SCV000583865.1, Esser 1988, Amsellem 2002). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 3688) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In vitro functional studies support an impact on protein function (Esser 1988). Additional variants involving this codon (p.Gly565Asp and p.Gly565Ala) have been identified in individuals with FH. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly565 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11313767, 27784735), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects LDLR function (PMID: 2901412, 16740646). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 3688). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2901412, 12436241, 23375686). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 565 of the LDLR protein (p.Gly565Val).

The c.1694G>T (p.Gly565Val) variant in LDLR gene, that encodes for low density lipoprotein receptor, has been identified in at least five individuals who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID:12436241, 23375686, 32770674, 28161202). This variant has also been reported in homozygous/compound heterozygous (with p.Trp4*) status in individuals with severe FH (PMID: 27784735, 6299582). This variant has also been detected in hypercholesterolemia cohorts and cohorts referred for FH testing (PMID: 34037665, 34297352). Experimental studies on transfected CHO cells demonstrated that this variant caused complete retention of protein on the endoplasmic reticulum, severely affected LDLR surface expression, and no LDL particle internalization (PMID: 16740646, 16257961). In addition, studies on homozygous mutant cells showed LDLR activity of <2% compared to wild type (PMID: 1301956, 2901412, 6299582). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.971). This variant is found to be absent in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several submitters (10) in the ClinVar database (ClinVar ID: 3688). Other amino acid substitutions at the same codon (p.Gly565Arg, p.Gly565Asp, p.Gly565Ala) have been reported in individuals with FH (PMID: 33994402, 27784735, 11313767) and classified as likely pathogenic by ClinVar submitters (ClinVar ID: 1778186, 375819, 226366). Therefore, the c.1694G>T (p.Gly565Val) variant in LDLR gene is classified as likely pathogenic.

The p.G565V pathogenic mutation (also known as c.1694G>T), located in coding exon 11 of the LDLR gene, results from a G to T substitution at nucleotide position 1694. The glycine at codon 565 is replaced by valine, an amino acid with dissimilar properties. This variant (also referred to as p.G544V) has been detected in individuals reported to have homozygous or heterozygous familial hypercholesterolemia (FH), and assays on homozygous patient cells reportedly showed LDLR activity of <2% compared to wild type (Esser V et al. J Biol Chem, 1988 Sep;263:13276-81; Hobbs HH et al. Hum Mutat, 1992;1:445-66; Amsellem S et al. Hum Genet, 2002 Dec;111:501-10; Rieck L et al. Clin Genet, 2020 11;98:457-467). This variant was also detected in additional hypercholesterolemia cohorts and cohorts referred for FH testing (Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Di Taranto MD et al. Clin Genet, 2021 11;100:529-541; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). Several In vitro studies indicate that this variant results in LDLR protein that is retained in the endoplasmic reticulum, not reaching the plasma membrane (Esser V et al. J Biol Chem, 1988 Sep;263:13276-81; Tveten K et al. FEBS J, 2007 Apr;274:1881-93; Oka OB et al. Mol Cell, 2013 Jun;50:793-804; Du&scaron;kov&aacute; L et al. Front Genet, 2020 Jun;11:691; Lebeau PF et al. J Clin Invest, 2021 01;131). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.