Submissions for variant NM_000527.5(LDLR):c.1284C>G (p.Asn428Lys)

dbSNP: rs368708058

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238106	SCV000295340	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV001526181	SCV001736482	likely pathogenic	Familial hypercholesterolemia	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 428 of the LDLR protein. This variant is also known as p.Asn407Lys in the mature protein. This variant alters a conserved asparagine residue in the LDLR type B repeat 1 of the LDLR protein (a.a. 397-438), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 11005141, 11668640, 11845603, 11857755, 14508510, 15556094, 21382890, 35047021, 36499307). This variant has also been observed in compound heterozygous state with known pathogenic LDLR variants in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 36980993; Callis 2000 dissertation, University of the Orange Free State). It has been shown that this variant segregates with disease in multiple heterozygous affected relatives in one family (Callis 2000 dissertation, University of the Orange Free State). This variant has been detected in over 30 Dutch individuals showing modest severity of hypercholesterolemia with mean LDL-C levels in the 75-88th percentile according to the Dutch Lipid Clinic Network criteria (Hartgers 2020 dissertation, University of Amsterdam). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV001526181	SCV002284046	pathogenic	Familial hypercholesterolemia	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 428 of the LDLR protein (p.Asn428Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant familial hypercholesterolemia (PMID: 11005141, 11238294, 11668640, 11857755; Invitae). This variant is also known as N407K. ClinVar contains an entry for this variant (Variation ID: 251766). 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003165668	SCV003907261	likely pathogenic	Inborn genetic diseases	2023-03-20	criteria provided, single submitter	clinical testing	The c.1284C>G (p.N428K) alteration is located in exon 9 (coding exon 9) of the LDLR gene. This alteration results from a C to G substitution at nucleotide position 1284, causing the asparagine (N) at amino acid position 428 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant (also referred to as p.N407K) has been detected in several unrelated individuals with familial hypercholesterolemia (FH) (Khoo, 2000; Fouchier, 2001; van der Graaf, 2011; García-García, 2001; Bunn, 2002; Rimbert, 2021; Razman, 2022). This variant has also been detected in additional FH and dyslipidemia cohorts (Vergotine, 2001; Murdock, 2021). In one study, this variant co-occurred with an APOB variant in a proband reported to have more severe hypercholesterolemia than relatives with only one variant (Tai, 2001; Taylor, 2010). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238106	SCV000606380	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research