Submissions for variant NM_000527.5(LDLR):c.1829C>T (p.Ser610Phe)

dbSNP: rs879255038

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237403	SCV000295684	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237403	SCV000503419	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2/Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237403	SCV000583887	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411093	SCV002711140	likely pathogenic	Cardiovascular phenotype	2017-07-28	criteria provided, single submitter	clinical testing	The p.S610F variant (also known as c.1829C>T), located in coding exon 12 of the LDLR gene, results from a C to T substitution at nucleotide position 1829. The serine at codon 610 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with familial hypercholesterolemia (Jensen HK et al. Atherosclerosis. 1999;146:337-44 (reported as S589F)). Internal structural analysis predicts this alteration to be disruptive to the protein domain (Lo Surdo P et al. EMBO Rep. 2011;12(12):1300-5). In addition, another change affecting this amino acid (p.S610C) has also been reported in association with hypercholesterolemia (Dušková L et al. Atherosclerosis. 2011;216:139-45). This amino acid position is well conserved in available vertebrate species, and is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV003581633	SCV004298373	likely pathogenic	Familial hypercholesterolemia	2023-08-22	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser610 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 252055). This variant is also known as S589F. This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 10532689, 31491741). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 610 of the LDLR protein (p.Ser610Phe).