Submissions for variant NM_000527.5(LDLR):c.590G>T (p.Cys197Phe)

dbSNP: rs376459828

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238173	SCV002506407	likely pathogenic	Hypercholesterolemia, familial, 1	2022-03-09	reviewed by expert panel	curation	NM_000527.5(LDLR):c.590G>T (p.Cys197Phe) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2 PP1, PP3_Supporting 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: PM2 - PopMax MAF = 0.00006 (0.006%) in African exomes (gnomAD v2.1.1). PP3 - REVEL = 0.945. It is above 0.75 PM1 - Variant meets PM2 and located in highly conserved Cystein 197. PP1_Moderate - Variant segregate with phenotype in 4 informative meioses in 1 family. PP4 - Variant meets PM2 and is identified in 1 index case who fulfil SB criteria for FH (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge)
LDLR-LOVD, British Heart Foundation	RCV000238173	SCV000294807	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238173	SCV000322904	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles
Fulgent Genetics, Fulgent Genetics	RCV000238173	SCV000894169	likely pathogenic	Hypercholesterolemia, familial, 1	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001068108	SCV001233198	pathogenic	Familial hypercholesterolemia	2022-12-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys197 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20809525, 23375686, 27816806), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). 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. ClinVar contains an entry for this variant (Variation ID: 251309). This missense change has been observed in individuals with clinical features of hypercholesterolemia (PMID: 1301956, 20828696, 24507775; Invitae). This variant is present in population databases (rs376459828, gnomAD 0.007%). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 197 of the LDLR protein (p.Cys197Phe).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001068108	SCV001422744	uncertain significance	Familial hypercholesterolemia	2020-01-23	criteria provided, single submitter	curation	The p.Cys197Phe variant in LDLR has been reported in 1 Portuguese and 1 African American individual with familial hypercholesterolemia (PMID: 20828696, 1301956), and has been identified in 0.006% (1/16232) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376459828). This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 251309). In vitro functional studies provide some evidence that the p.Cys197Phe variant may slightly impact protein function (PMID: 1301956). 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. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Cys197Tyr, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 27816806, 14993243, 1301956, 23064986, 21376320, 18096825/Variation ID: 200919). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PS4_supporting, PS3_supporting, PM5_supporting (Richards 2015).
Ambry Genetics	RCV002356330	SCV002652596	pathogenic	Cardiovascular phenotype	2018-01-23	criteria provided, single submitter	clinical testing	The p.C197F pathogenic mutation (also known as c.590G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 590. The cysteine at codon 197, located in LDLR class A repeat 5, is replaced by phenylalanine, 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 alteration, also referred to as FH Shreveport or C176F, has been reported in association with FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 5. In addition, other alterations affecting this amino acid (C197Y, C197W, C197G, C197R) have also been described in association with FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Chmara M et al. J Appl Genet. 2010;51(1):95-106; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238173	SCV000606166	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research