Submissions for variant NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg)

gnomAD frequency: 0.00001  dbSNP: rs748554592

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238583	SCV002506354	uncertain significance	Hypercholesterolemia, familial, 1	2022-03-07	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_supporting, PP3 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 = 0.0001088 (0.01088%) in East Asian exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.822. PS4_supporting - Variant meets PM2. Variant identified in 4 unrelated index cases (3 cases with Simon-Broome published in PMID: 9763532; 1 case with DLCN criteria from Robarts Research Institute. PP4 - Variant meets PM2. Variant identified in 4 FH cases (3 cases with Simon-Broome Definite published in PMID: 9763532; 1 case with DLCN criteria = > 6 from Robarts Research Institute.
LDLR-LOVD, British Heart Foundation	RCV000238583	SCV000295319	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000238583	SCV000484747	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775061	SCV000909162	likely pathogenic	Familial hypercholesterolemia	2019-03-22	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Leu393Arg in the mature protein) replaces leucine with arginine at codon 414 in the first EGF-like repeat B in the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 26608663, 26875521, 27765764, 29353225, 9763532). This variant has been identified in 2/251172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000775061	SCV001360702	pathogenic	Familial hypercholesterolemia	2019-07-08	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1241T>G (p.Leu414Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251172 control chromosomes. c.1241T>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Mak_1998, Kondkar_2007, Chiou_2017, Chan_2018, Pek_2018), predominantly in individuals from Asian origin. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cite variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000238583	SCV001432554	pathogenic	Hypercholesterolemia, familial, 1	2019-03-13	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775061	SCV001575511	pathogenic	Familial hypercholesterolemia	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 414 of the LDLR protein (p.Leu414Arg). This variant is present in population databases (rs748554592, gnomAD 0.01%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9452118, 27765764). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as L393R. ClinVar contains an entry for this variant (Variation ID: 251747). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV004020961	SCV004076761	likely pathogenic	Cardiovascular phenotype	2023-07-13	criteria provided, single submitter	clinical testing	The c.1241T>G (p.L414R) alteration is located in exon 9 (coding exon 9) of the LDLR gene. This alteration results from a T to G substitution at nucleotide position 1241, causing the leucine (L) at amino acid position 414 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.001% (2/251172) total alleles studied. The highest observed frequency was 0.011% (2/18384) of East Asian alleles. This variant was identified in trans with a second LDLR variant in twins presenting with elevated LDL-C levels and multiple xanthomas (Zhang, 2022). In addition, this variant has been identified alone in multiple individuals with familial hypercholesterolemia (Mak, 1998; Mak, 1998; Kondkar, 2007; Chiou, 2017; Pek, 2018; Chan, 2019; Huang, 2022). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477854	SCV004219940	likely pathogenic	not provided	2023-09-20	criteria provided, single submitter	clinical testing	The LDLR c.1241T>G (p.Leu414Arg) variant has been reported in the published literature in multiple individuals affected with familial hypercholesterolemia (PMIDs: 9763532 (1998), 11005141 (2000), 18022922 (2007), 26875521 (2016), 30592178 (2019), 33994402 (2021), 35130036 (2022), 36229885 (2022), 36325061 (2022)). The frequency of this variant in the general population, 0.000008 (2/251172 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238583	SCV000606369	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research