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

dbSNP: rs368708058

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238106	SCV005375286	uncertain significance	Hypercholesterolemia, familial, 1	2023-06-23	reviewed by expert panel	curation	The NM_000527.5 (LDLR):c.1284C>G (p.Asn428Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: Variant is absent from gnomAD (gnomAD v2.1.1). PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 5 index cases who fulfill criteria for FH (1 case with total cholesterol >8 mmol/L and family history of hypercholesterolemia or classical clinical stigmata of FH from PMID 11857755 (Bunn et al., 2002), New Zealand; 1 case with total cholesterol >90th percentile and clinical features of FH or family history of early CHD from PMID 11845603 (Vergotine et al., 2001), South Africa; 1 case with DLCN score >=6 from PMID 11810272 (Fouchier et al., 2001), the Netherlands; 1 case with LDL >95th percentile, plus two of: presence of xanthomata, CAD in proband or family history of CAD or high LDL, from PMID 11668640 (Garcia-Garcia et al., 2001) Spain; 1 case with LDLC 6.5 mmol/L, presence of xanthomas, and history of angioplasty or bypass surgery from PMID 11005141 (Khoo et al., 2000), Malaysia.
LDLR-LOVD, British Heart Foundation	RCV001526181	SCV000295340	uncertain significance	Familial hypercholesterolemia	2016-03-25	criteria provided, single submitter	literature only	Re-evaluation of ACMG classification, scoring: PM2, PS4_supporting, PP4. PP3 could not be scored as the score of 0.718 is below the threshold of >0.75. At least 5 unrelated cases of confirmed FH carry this variant. Many further cases have been reported, however, the classification of their diagnosis is not well defined, so PS4 moderate or strong could not be scored.
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.
Labcorp Genetics (formerly Invitae), Labcorp	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	RCV004020963	SCV003907261	likely pathogenic	Cardiovascular phenotype	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.
All of Us Research Program, National Institutes of Health	RCV000238106	SCV004820288	likely pathogenic	Hypercholesterolemia, familial, 1	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asn407Lys in the mature protein) replaces asparagine with lysine at codon 428 in the LDLR type B repeat 1 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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). Heterozygous relatives of one of these individuals were also affected with hypercholesterolemia (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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526181	SCV005205210	likely pathogenic	Familial hypercholesterolemia	2024-06-27	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1284C>G (p.Asn428Lys; also known as N407K in the literature) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251288 control chromosomes (gnomAD). c.1284C>G has been reported in the literature in both heterozygous and compound heterozygous individuals affected with familial hypercholesterolemia (FH; example: Bunn_2002, Khoo_2000, Razman_2022, Reijman_2023, Rimbert_2022, Sjouke_2015). The variant was also reported to co-occur with another pathogenic APOB variant in an individual who was affected with both FH and familial defective apolipoprotein B-100. This individual had a more severe phenotype than her siblings who carried only one variant (Tai_2001). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36499307, 36752612, 11005141, 11857755, 35047021, 27919364, 11238294). ClinVar contains an entry for this variant (Variation ID: 251766). Based on the evidence outlined above, the variant was 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