Submissions for variant NM_000527.5(LDLR):c.1216C>A (p.Arg406=)

dbSNP: rs121908043

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000003944	SCV001960923	likely pathogenic	Hypercholesterolemia, familial, 1	2021-06-08	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1216C>A (p.Arg406=) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS3_Moderate, PP4 and PS4_Supportive) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00005441 (0.005%) in East Asian exomes (gnomAD v2.1.1). PM3 - Variant meets PM2 and is identified in one compound heterozygote with a homozygous FH phenotype published in PMID 28028493 (Patient F3 compound with NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) (ClinVar ID 251436), LDLc: 18.21 mmol/l). Additional variant classified as Pathogenic by these guidelines. PS3_moderate - Level 2 FS: PMID: 19371225 - Htz patient's Epstein-Barr virus transformed lymphocytes. RNA assays. Mutant mRNA 25%-45% of total amount. PP4 - Variant meets PM2. Variant identified in 2 index cases. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases.
LDLR-LOVD, British Heart Foundation	RCV000003944	SCV000295305	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000003944	SCV000599368	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588218	SCV000697190	pathogenic	Familial hypercholesterolemia	2017-07-10	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1216C>A (p.Arg406Arg) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing by the introduction of a cryptic splice site and ESE finder predicts that this variant may affect ESE sites at the locus. In support of these predictions, functional studies have shown that the variant splice site is used preferentially over the wild type splice site in patient cell lines and in vitro splicing assays (Tveten_Genet Test Molec Biomarkers_2009; Bourbon_Ather_2007). Additionally, the variant has been cited in numerous patients with hypercholesterolemia and segregates with disease in families (e.g., van der Graaf_Circ_2011; Du_SpringerPlus_2016; Tveten_Genet Test Molec Biomarkers_2009). This variant is absent from the large control database ExAC and control cohorts from the literature (0/120510 control chromosomes). In addition, two reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000588218	SCV000833922	pathogenic	Familial hypercholesterolemia	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change affects codon 406 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs121908043, gnomAD 0.006%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 17094996, 17335829, 19371225, 21382890, 28028493). ClinVar contains an entry for this variant (Variation ID: 3746). Studies have shown that this variant results in a deletion of 31 base pairs of exon 9 and introduces a premature termination codon (PMID: 17335829, 19371225). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000588218	SCV001349490	pathogenic	Familial hypercholesterolemia	2023-05-08	criteria provided, single submitter	clinical testing	This variant changes a single nucleotide in exon 9 (c.1216C>A) of the LDLR gene and has been shown to create a new splice acceptor site. RNA studies in cells from familial hypercholesterolemia subjects have shown that the usage of the newly created splice acceptor causes a deletion of 31 nucleotides from the beginning of exon 9 of the LDLR gene, leading to frameshift and premature truncation of the mutant allele (PMID: 17335829, 18400033). As a result, normal transcript is not produced from the mutant allele. This variant has been identified in multiple individuals diagnosed with familial hypercholesterolemia, mostly of Chinese origin (PMID: 17094996, 17335829, 18400033, 19371225, 21382890, 28028493, 28235710, 30270083, 31345425, 34037665, 34297352). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 36325061). This variant has been identified in 1/245992 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant at the same position (c.1216C>T) is also shown to cause splice defect (PMID: 28169869). Based on available evidence, this variant is classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000003944	SCV001432549	likely pathogenic	Hypercholesterolemia, familial, 1	2019-03-03	criteria provided, single submitter	research
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000003944	SCV001433518	pathogenic	Hypercholesterolemia, familial, 1	2019-12-30	criteria provided, single submitter	clinical testing
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000003944	SCV001653629	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing	altered splicing
Ambry Genetics	RCV002354146	SCV002661083	pathogenic	Cardiovascular phenotype	2021-03-22	criteria provided, single submitter	clinical testing	The c.1216C>A pathogenic mutation (also known as p.R406R) is located in coding exon 9 of the LDLR gene. This variant results from a C to A substitution at nucleotide position 1216. This nucleotide substitution does not change the arginine at codon 406. This alteration has been reported in the heterozygous and compound heterozygous state in multiple individuals with heterozygous and homozygous familial hypercholesterolemia, respectively (Defesche JC et al. Clin Genet, 2008 Jun;73:573-8; Fan LL et al. Appl Biochem Biotechnol, 2015 May;176:101-9; Du R et al. Springerplus, 2016 Dec;5:2095; Jiang L et al. J Clin Lipidol 2016 Dec;10:538-546.e5; Xiang R et al. Atherosclerosis, 2017 03;258:84-88; Hsiung YC et al. Atherosclerosis, 2018 10;277:440-447). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site, and multiple functional studies indicate that the created cryptic acceptor site is preferentially utilized, resulting in a deletion of 31 nucleotides from the beginning of exon 9 and a frameshift (Bourbon M et al. Atherosclerosis, 2007 Nov;195:e17-20; Defesche JC et al. Clin Genet, 2008 Jun;73:573-8; Tveten K et al. Genet Test Mol Biomarkers, 2009 Apr;13:243-8). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000003944	SCV000024109	pathogenic	Hypercholesterolemia, familial, 1	2008-06-01	no assertion criteria provided	literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003944	SCV000606361	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research