Submissions for variant NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe)

dbSNP: rs934496989

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000505204	SCV005328523	likely pathogenic	Hypercholesterolemia, familial, 1	2023-11-07	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4, PS3_Supporting and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3: REVEL=0.907. PS3_Supporting: Level 3 assay: PMID 35474963 (Pfisterer SG et al., 2022): Heterozygous patient monocytes and lymphocytes. 25-50% of control low-density lipoprotein particle uptake and LDLR surface expression. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill DLCN score >=6 (1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca). PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca. 1 affected family member has the variant and 1 unaffected family member does not have the variant.
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000505204	SCV000599390	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV001053021	SCV001217263	pathogenic	Familial hypercholesterolemia	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 580 of the LDLR protein (p.Ser580Phe). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of autosomal dominant and autosomal recessive familial hypercholesterolemia (PMID: 21865347, 31947532, 32977124; Invitae). ClinVar contains an entry for this variant (Variation ID: 438325). 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%. For these reasons, this variant has been classified as Pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000505204	SCV001653651	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002404318	SCV002710232	likely pathogenic	Cardiovascular phenotype	2022-02-02	criteria provided, single submitter	clinical testing	The p.S580F variant (also known as c.1739C>T), located in coding exon 12 of the LDLR gene, results from a C to T substitution at nucleotide position 1739. The serine at codon 580 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration is located immediately adjacent to the YWTD motif in the LDLR class B repeat 5. This variant has been previously reported in both the heterozygous and compound heterozygous states (with LDLR p.G549D and p.G592E mutations) in individuals reported to have a clinical diagnosis of familial hypercholesterolemia (Romano M et al. J. Lipid Res. 2011;52:2095-100; Di Taranto MD et al. J Clin Med. 2020 Jan;9(1); Di Taranto MD et al. Clin Genet. 2021 11;100(5):529-541). LDLR activity was reduced in lymphocytes derived from both heterozygous and a compound heterozygous individuals, with cells from the heterozygous patient exhibiting ~65% of the LDLR activity in control cells and cells from a compound heterozygote displaying 30-40% of control LDLR activity (Romano M et al. J. Lipid Res. 2011;52:2095-100). Internal structural analysis predicts that this variant results in a significant decrease in structural stability (Jeon H et al. Nat Struct Biol. 2001 Jun;8(6):499-504; Ambry internal data). 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, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001053021	SCV004359041	likely pathogenic	Familial hypercholesterolemia	2022-06-07	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Ser559Phe in the mature protein) replaces serine with phenylalanine at codon 580 in the LDLR type B repeat 5 in the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in nine unrelated individuals affected with familial hypercholesterolemia (PMID: 21865347, 34297352, Schoen et al. 2014 doi:10.1016/j.jacl.2014.02.029). This variant has also been observed in the compound heterozygous state with other pathogenic LDLR variants (p.Gly549Asp, p.Gly592Glu) in two unrelated individuals affected with homozygous familial hypercholesterolemia (PMID: 21865347, 31947532). Reduced LDL uptake activities were observed in leukocytes from two of the affected carriers (PMID: 21865347, 35474963). This variant has been identified in 1/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.