rs774723292
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.343C>T (p.Arg115Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3 and PP4) 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: PM1 - Missense at codon 115. Variant meets PM2 and is in exon 4.PM2 - FAF = 0.0001446 (0.014%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3 - REVEL = 0.81. PP4 - Variant meets PM2. Identified in at least 1 FH case with clinical diagnosis of definite heterozygous hypercholesterolemia by DLCN score from PMID 16250003. LINK:https://erepo.genome.network/evrepo/ui/classification/CA043225/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.343C>T | p.Arg115Cys | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.343C>T | p.Arg115Cys | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250716Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135750
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461240Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15AN XY: 726948
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:9Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Dec 16, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 07, 2021 | ACMG classification criteria: PS4, PM2, PP1, PP3 - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Arg115Cys variant in LDLR has been reported in at least 5 individuals (including 1 Dutch individual) with Familial Hypercholesterolemia, segregated with disease in 5 affected relatives from 2 families (PMID: 16250003; Variation ID: 251162), and has been identified in 0.01446% (5/34586) of Latino chromosomes and 0.005446% (1/18362) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs774723292). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported as a VUS, likely pathogenic variant, and a pathogenic variant in ClinVar (Variation ID: 251162). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP1_Moderate, PP3, PS4_Supporting (Richards 2015). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 12, 2023 | The LDLR c.343C>T (p.Arg115Cys) missense variant has been identified in individuals with familial hypercholesterolemia; however, clinical details are limited (PMID:16250003;33418990). This variant is located in the LDLR class A repeat, a component of the well-established ligand (LDL) binding domain within exon 4. The p.Arg115Cys variant results in a substitution of arginine by cysteine, which may affect disulfide bond formation and protein folding (PMID: 34906454). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. The p.Arg115Cys variant has been classified as likely pathogenic by at least three submitters in ClinVar including the ClinGen familial hypercholesterolemia variant curation expert panel. Based on the available evidence, the c.343C>T (p.Arg115Cys) variant is classified as likely pathogenic for familial hypercholesterolemia. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | This missense variant replaces arginine with cysteine at codon 115 of the LDLR protein. This variant is also known as p.Arg94Cys in the mature protein. This variant is located in the type A repeat 3 ligand binding domain (aa 107-145) 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). A functional study using a pig model has shown that this variant disrupts LDLR activity (PMID: 10064736). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 30270359, 34074024, 33418990) in the literature, including three hypercholesterolemic individuals in one family (PMID: 30270359). This variant has also been reported in affected individuals by external laboratories (ClinVar submission SCV000583664.1, SCV000503143.1, SCV001482448.1). This variant has been identified in 7/250716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 25, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Jun 07, 2021 | The NM_000527.5(LDLR):c.343C>T (p.Arg115Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3 and PP4) 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: PM1 - Missense at codon 115. Variant meets PM2 and is in exon 4. PM2 - FAF = 0.0001446 (0.014%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3 - REVEL = 0.81. PP4 - Variant meets PM2. Identified in at least 1 FH case with clinical diagnosis of definite heterozygous hypercholesterolemia by DLCN score from PMID 16250003. - |
Familial hypercholesterolemia Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | research | Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 13, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 115 of the LDLR protein (p.Arg115Cys). This variant is present in population databases (rs774723292, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 16250003, 33418990). ClinVar contains an entry for this variant (Variation ID: 251162). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 03, 2023 | This missense variant replaces arginine with cysteine at codon 115 of the LDLR protein. This variant is also known as p.Arg94Cys in the mature protein. This variant is located in the type A repeat 3 ligand binding domain (aa 107-145) 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). A functional study using a pig model has shown that this variant disrupts LDLR activity (PMID: 10064736). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16250003, 30270359, 34074024, 33418990) in the literature, including three hypercholesterolemic individuals in one family (PMID: 30270359). This variant has also been reported in affected individuals by external laboratories (ClinVar submission SCV000583664.1, SCV000503143.1, SCV001482448.1). This variant has been identified in 7/250716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 08, 2023 | Reported as likely pathogenic by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel in ClinVar (Accession: SCV001960959.1); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19544207, 10064736, 30270359, 30583242, 34906454, 33418990, 16250003) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 05, 2024 | The c.343C>T (p.R115C) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 343, causing the arginine (R) at amino acid position 115 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at