ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect through abnormal ligand binding and receptor internalization (Plewa et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as C152W; This variant is associated with the following publications: (PMID: 9452094, 10090484, 11810272, 26343872, 9544726, 34456200, 32044282, 11462246, 25962062, 34037665, 28619117, 16502360, 33418990, 34182004, 34875256)

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the LDLR protein (p.Cys173Trp). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9452094, 11462246, 11810272, 25962062). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys152Trp. ClinVar contains an entry for this variant (Variation ID: 251277). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Cys173 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7489239, 20019594). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected and unaffected individuals from a single family.

This missense variant (also known as p.Cys152Trp in the mature protein) replaces cysteine with tryptophan at codon 173 in the LDLR type A repeat 4 in the ligand binding domain of the LDLR protein. This variant alters one of the highly conserved cysteine residues that are critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in a significant decrease in LDL binding and internalization (PMID: 9544726, 16502360). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 11462246, 11810272, 25962062, 31345425, 32044282, 32220565) and has been shown to segregate with hypercholesterolemia in over ten individuals from two unrelated families (PMID: 9452094, 9544726). This variant has been identified in 2/251308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Variant summary: LDLR c.519C>G (p.Cys173Trp) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251308 control chromosomes (gnomAD). c.519C>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and has been shown to segregate with disease in several affected individuals within two unrelated families (e.g. Couture_1998, Morash_1998, Ebhardt_1999, Fouchier_2001, Nauck_2001, Plewa_2006). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant results in a significant decrease in LDL binding capacity (Morash_1998, Plewa_2006). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.C173W pathogenic mutation (also known as c.519C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 519. The cysteine at codon 173 is replaced by tryptophan, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This mutation, which is also known as p.C152W, has been reported in multiple individuals with FH and was observed to segregate with elevated LDL-levels across two generations in one family (Couture P et al. Hum Mutat, 1998;Suppl 1:S226-31; Morash BA et al. Atherosclerosis, 1998 Jan;136:9-16; Ebhardt M et al. Hum Mutat, 1999;13:257; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Nauck MS et al. Hum Mutat, 2001 Aug;18:165-6; Shin DG et al. Atherosclerosis, 2015 Nov;243:53-8; Meshkov A et al. Genes (Basel), 2021 01;12:[ePub ahead of print]; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 4 (Ambry internal data). This alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified: - p.C173W (c.519C>G) in the LDLR gene. The lab classifies this as a pathogenic mutation. Given sufficient case data and it's disruption of the binding site of the low density lipoprotein receptor protein we consider this variant likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least five unrelated cases of familial hypercholesterolemia (not including this patient's family). There is two generation segregation data presented in one family with four affected individuals. Couture, et al., 1998 reported a novel variant p.C173W (reported as p.C152W and c.519C>G in the paper). The C-to-G transversion at nucleotide 519 results in a change in the highly conserved cysteine at the C-terminal end in the fourth of the seven tandem cysteine repeats that for the binding site for LDLR (Bieri et al., 1995; Mehta et al., 1991). They variant segregated with FH in four individuals who had LDLs of 178, 298, 200 and 263, three of whom had tendinous xanthomas and two of which had coronary artery disease. Ebhardt, et al., 1999 reported a patient with p.C173W (reported as p.C152W and c.519C>G in the paper) in a Northern German individual that segregated with FH in the family (no details on number of individuals). Fouchier, et al., 2001; Morash, et al., 1998; Nauck, et al., 1997 all reported a patient with p.C173W (reported as p.C152W). The do not offer clinical details other than each patient had a diagnosis of familial hypercholesterolemia. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 1.00) and Mutation Taster predicts that it's disease causing (0.999). The cysteine at codon 173 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (C152R in a greek patient with compound heterozygous FH) and nearby codons (167, 175, and 177 in clinvar). In total the variant has not been seen in 100 published controls and individuals from publicly available population datasets. There is no missense variation at codon 173 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 24, 2015). There were 16,512 individuals of South Asian descent.